Use of substituted N, N-disubstituted diamino compounds for inhibiting cholesteryl ester transfer protein activity

ABSTRACT

The invention relates to substituted polycyclic aryl and heteroaryl tertiary-heteroalkylamine compounds useful as inhibitors of cholesteryl ester transfer protein (CETP; plasma lipid transfer protein-I) and compounds, compositions and methods for treating atherosclerosis and other coronary artery diseases. Preferred tertiary-heteroalkylamine compounds are substituted N,N-disubstituted diamines. A preferred specific N,N-disubstituted diamine is the compound:

RELATED APPLICATIONS

This is a divisional of pending U.S. patent application Ser. No.09/405,524, filed Sep. 23, 1999.

FIELD OF THE INVENTION

This invention is in the field of treating cardiovascular disease, andspecifically relates to compounds, compositions and methods for treatingatherosclerosis and other coronary artery disease. More particularly,the invention relates to substituted polycyclic aryl and heteroaryltertiary-heteroalkylamine compounds that inhibit cholesteryl estertransfer protein (CETP), also known as plasma lipid transfer protein-I.

BACKGROUND OF THE INVENTION

Numerous studies have demonstrated that a low plasma concentration ofhigh density lipoprotein (HDL) cholesterol is a powerful risk factor forthe development of atherosclerosis (Barter and Rye, Atherosclerosis,121, 1-12 (1996)). HDL is one of the major classes of lipoproteins thatfunction in the transport of lipids through the blood. The major lipidsfound associated with HDL include cholesterol, cholesteryl ester,triglycerides, phospholipids and fatty acids. The other classes oflipoproteins found in the blood are low density lipoprotein (LDL) andvery low density lipoprotein (VLDL). Since low levels of HDL cholesterolincrease the risk of atherosclerosis, methods for elevating plasma HDLcholesterol would be therapeutically beneficial for the treatment ofatherosclerosis and other diseases associated with accumulation of lipidin the blood vessels. These diseases include, but are not limited to,coronary heart disease, peripheral vascular disease, and stroke.

Atherosclerosis underlies most coronary artery disease (CAD), a majorcause of morbidity and mortality in modem society. High LDL cholesterol(above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have beenshown to be important contributors to the development ofatherosclerosis. Other diseases, such as peripheral vascular disease,stroke, and hypercholesterolaemia are negatively affected by adverseHDL/LDL ratios. Inhibition of CETP by the subject compounds is shown toeffectively modify plasma HDL/LDL ratios, and to check the progressand/or formation of these diseases.

CETP is a plasma protein that facilitates the movement of cholesterylesters and triglycerides between the various lipoproteins in the blood(Tall, J. Lipid Res., 34, 1255-74 (1993)). The movement of cholesterylester from HDL to LDL by CETP has the effect of lowering HDLcholesterol. It therefore follows that inhibition of CETP should lead toelevation of plasma HDL cholesterol and lowering of plasma LDLcholesterol, thereby providing a therapeutically beneficial plasma lipidprofile (McCarthy, Medicinal Res. Revs., 13, 139-59 (1993); Sitori,Pharmac. Ther., 67,443-47 (1995)). This exact phenomenon was firstdemonstrated by Swenson et al., (J. Biol. Chem., 264, 14318 (1989)) withthe use of a monoclonal antibody that specifically inhibited CETP. Inrabbits, the antibody caused an elevation of the plasma HDL cholesteroland a decrease in LDL cholesterol. Son et al. (Biochim. Biophys. Acta795, 743-480 (1984)), Morton et al. (J. Lipid Res. 35, 836-847 (1994))and Tollefson et al. (Am. J. Physiol., 255, (Endocrinol. Metab. 18,E894-E902 (1988))) describe proteins from human plasma that inhibitCETP. U.S. Pat. No. 5,519,001, issued to Kushwaha et al., describes a 36amino acid peptide derived from baboon apo C-1 that inhibits CETPactivity. Cho et al. (Biochim. Biophys. Acta 1391, 133-144 (1998))describe a peptide from hog plasma that inhibits human CETP. Bonin etal. (J. Peptide Res., 51, 216-225 (1998)) disclose a decapeptideinhibitor of CETP. A depsipeptide fungal metabolite is disclosed as aCETP inhibitor by Hedge et al. in Bioorg. Med. Chem. Lett., 8, 1277-80(1998).

There have been several reports of non-peptidic compounds that act asCETP inhibitors. Barrett et al. (J. Am. Chem. Soc., 188, 7863-63 (1996))and Kuo et al. (J. Am. Chem. Soc., 117, 10629-34 (1995)) describecyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. Med.Chem. Lett, 6, 1951-54 (1996)) describe phosphonate-containing analogsof cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. Med.Chem. Lett., 5, 605-610 (1995)) describe Wiedendiol-A and -B, andrelated sesquiterpene compounds as CETP inhibitors. Japanese PatentApplication No. 10287662-A describes polycyclic, non-amine containing,polyhydroxylic natural compounds possessing CETP inhibition properties.Lee et al. (J. Antibiotics, 49, 693-96 (1996)) describe CETP inhibitorsderived from an insect fungus. Busch et al. (Lipids, 25, 216-220,(1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Mortonand Zilversmit (J. Lipid Res., 35, 836-47 (1982)) describe thatp-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethylmercurithiosalicylate inhibit CETP. Connolly et al. (Biochem. Biophys.Res. Comm. 223, 42-47 (1996)) describe other cysteine modificationreagents as CETP inhibitors. Xia et al. describe 1,3,5-triazines as CETPinhibitors (Bioorg. Med. Chem. Lett., 6, 919-22 (1996)). Bisgaier et al.(Lipids, 29, 811-8 (1994)) describe4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor. Oomuraet al. disclose non-peptidic tetracyclic and hexacyclic phenols as CETPinhibitors in Japanese Patent Application No. 10287662. In WO PatentApplication No. 09914204, Sikorski describes 1,2,4-triazolylthiolsuseful as chlolesteryl ester transfer protein inhibitors.

Some substituted heteroalkylamine compounds are known. In EuropeanPatent Application No. 796846, Schmidt et al. describe2-aryl-substituted pyridines as cholesteryl ester transfer proteininhibitors useful as cardiovascular agents. One substitutent at C3 ofthe pyridine ring can be an hydroxyalkyl group. In European PatentApplication No. 801060, Dow and Wright describe heterocyclic derivativessubstituted with an aldehyde addition product of an alkylamine to afford1-hydroxy-1-amines. These are reported to be β3-adrenergic receptoragonists useful for treating diabetes and other disorders. In GreatBritain Patent Application No. 2305665, Fisher et al. disclose 3-agonistsecondary amino alcohol substituted pyridine derivatives useful fortreating several disorders including cholesterol levels andartheroscierotic diseases. In European Patent Application No. 818448,Schmidt et al. describe tetrahydroquinoline derivatives as chlolesterylester transfer protein inhibitors. European Patent Application No.818197, Schmek et al. describe pyridines with fused heterocycles ascholesteryl ester transfer protein inhibitors. Brandes et al. in GermanPatent Application No. 19627430 describe bicyclic condensed pyridinederivatives as cholesteryl ester transfer protein inhibitors. In WOPatent Application No. 09839299, Muller-Gliemann et al. describequinoline derivatives as cholesteryl ester transfer protein inhibitors.U.S. Pat. No. 2,700,686, issued to Dickey and Towne, describesN-(2-haloalkyl-2-hydroxyethyl)amines in which the amine is furthersubstituted with either 1 to 2 aliphatic groups or one aromatic groupand one aliphatic group. U.S. Pat. No. 2,700,686 further describes aprocess to prepare the N-(2-haloalkyl-2-hydroxyethyl)amines by reactinghalogenated-1,2-epoxyalkanes with the corresponding aliphatic amines andN-alkylanilines and their use as dye intermediates.

SUMMARY OF THE INVENTION

The present invention provides compounds that can be used to inhibitcholesteryl ester transfer protein (CETP) activity and that have thegeneral structure:

In another aspect, the present invention includes pharmaceuticalcompositions comprising a pharmaceutically effective amount of thecompounds of this invention and a pharmaceutically acceptable carrier.

In another aspect, this invention relates to methods of using theseinhibitors as therapeutic agents in humans to inhibit cholesteryl estertransfer protein (CETP) activity, thereby decreasing the concentrationsof low density lipoprotein (LDL) and raising the level of high densitylipoprotein (HDL), resulting in a therapeutically beneficial plasmalipid profile. The compounds and methods of this invention can also beused to treat dyslipidemia (hypoalphalipoproteinemia),hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinemia),peripheral vascular disease, hypercholesterolaemia, atherosclerosis,coronary artery disease and other CETP-mediated disorders. The compoundscan also be used in prophylactic treatment of subjects who are at riskof developing such disorders. The compounds can be used to lower therisk of atherosclerosis. The compounds of this invention would be alsouseful in prevention of cerebral vascular accident (CVA) or stroke.Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals such as primates, rabbits, pigs, horses, and the like.

DESCRIPTION OF THE INVENTION

The present invention relates to a class of compounds comprisingsubstituted polycyclic aryl and heteroaryl tertiary-heteroalkylamineswhich are beneficial in the therapeutic and prophylactic treatment ofcoronary artery disease as given in Formula V-H (also referred to hereinas generic substituted polycyclic aryl and heteroaryl tertiaryomegaheteroalkylamines):

or a pharmaceutically acceptable salt thereof, wherein;

m is an integer selected from 0 through 5;

n is an integer selected from 0 through 5;

m plus n is an integer selected from 0 through 6;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl,haloalkoxyalkyl, and haloalkenyloxyalkyl;

X is selected from the group consisting of O, H, F, S, S(O), NH, N(OH),N(alkyl), and N(alkoxy);

R₁₆ is selected from the group consisting of hydrido, alkyl, alkenyl,alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl,alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl,alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl,haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy,dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl,dialkoxyphosphonoalkyl, trialkylsilyl, and a spacer selected from thegroup consisting of a covalent single bond and a linear spacer moietyhaving from 1 through 4 contiguous atoms linked to the point of bondingof an aromatic substituent selected from the group consisting of R₄, R₈,R₉, R₁₃, R₁₄, and R₁₅ to form a heterocyclyl ring having from 5 through10 contiguous members with the provisos that said spacer moiety is otherthan a covalent single bond when R₂ is alkyl and there is no R₁₆ whereinX is H or F;

D₁, D₂, J₁, J₂ and K₁ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one of D₁, D₂, J₁, J₂ and K₁ can be a covalent bond, no morethan one of D₁, D₂, J₁, J₂ and K₁ can be O, no more than one of D₁, D₂,J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalentbond when two of D₁, D₂, J₁, J₂ and K₁ are O and S, and no more thanfour of D₁, D₂, J₁, J₂ and K₁ can be N;

D₃, D₄, J₃, J₄ and K₂ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one of D₃, D₄, J₃, J₄ and K₂ can be a covalent bond, no morethan one of D₃, D₄, J₃, J₄ and K₂ can be O, no more than one of D₃, D₄,J₃, J₄ and K₂ can be S, one of D₃, D₄, J₃, J₄ and K₂ must be a covalentbond when two of D₃, D₄, J₃, J₄ and K₂ are O and S, and no more thanfour of D₃, D₄, J₃, J₄ and K₂ can be N;

R₂ is independently selected from the group consisting of hydrido,hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino, dialkylamino,alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl,haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl,arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl,cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl,cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

R₂ and R₃ can be taken together to form a linear spacer moiety selectedfrom the group consisting of a covalent single bond and a moiety havingfrom 1 through 6 contiguous atoms to form a ring selected from the groupconsisting of a cycloalkyl having from 3 through 8 contiguous members, acycloalkenyl having from 5 through 8 contiguous members, and aheterocyclyl having from 4 through 8 contiguous members;

R₂ and R₁₄ can be taken together to form a linear spacer moiety selectedfrom the group consisting of a covalent bond and a linear spacer moietyhaving from 1 through 5 contiguous atoms to form a heterocyclyl ringhaving from 5 through 8 contiguous members with the proviso that saidspacer group is other than —N═;

R₂ and R₁₅ can be taken together to form a linear spacer moiety selectedfrom the group consisting of a covalent bond and a linear spacer moietyhaving from 1 through 5 contiguous atoms to form a heterocyclyl ringhaving from 5 through 8 contiguous members with the proviso that saidspacer group is other than —N═;

R₂ and R₁₉ can be taken together to form a linear spacer moiety selectedfrom the group consisting of a covalent single bond and a linear moietyhaving from 1 through 5 contiguous atoms to form a ring selected fromthe group consisting of a cycloalkyl having from 3 through 8 contiguousmembers, a cycloalkylenyl having from 5 through 8 contiguous members,and a heterocyclyl having from 4 through 8 contiguous members;

R₂ and R₄, R₂ and R₈, R₂ and R₉, and R₂ and R₁₃ can be independentlyselected to form spacer pairs wherein a spacer pair is taken together toform a linear spacer moiety wherein said linear spacer moiety isselected to form a heterocyclyl ring having from 5 through 10 contiguousmembers;

R₃ is selected from the group consisting of hydrido, hydroxy, halo,cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acyl,sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl,alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroarylthio,aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,aroyl, heteroaroyl, aralkylthioalkyl, heteroaralkylthioalkyl,heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

R₃ and R₁₄ can be taken together to form a linear spacer moiety selectedfrom the group consisting of a covalent bond and a linear moiety havingfrom 1 through 5 atoms to form a heterocyclyl ring having from 5 through8 contiguous members;

R₃ and R₁₅ can be taken together to form a linear spacer moiety selectedfrom the group consisting of a covalent bond and a linear moiety havingfrom 1 through 5 atoms to form a heterocyclyl ring having from 5 through8 contiguous members;

R₃ and R₁₉ can be taken together to form a linear spacer moiety selectedfrom the group consisting of a covalent single bond and a linear moietyhaving a chain length of 1 to 5 atoms to form a ring selected from thegroup consisting of a cycloalkyl having from 3 through 8 contiguousmembers, a cycloalkylenyl having from 5 through 8 contiguous members,and a heterocyclyl having from 4 through 8 contiguous members;

R₃ and R₄, R₃ and R₈, R₃ and R₉, and R₃ and R₁₃ can be independentlyselected to form spacer pairs wherein a spacer pair is taken together toform a linear spacer moiety wherein said linear spacer moiety isselected to form a heterocyclyl ring having from 5 through 10 contiguousmembers;

Y is selected from a group consisting of a covalent single bond,(C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 4 and(CH(R₁₄))_(g)—W—(CH(R₁₄))_(p) wherein g and p are integers independentlyselected from 0 through 2;

R₁₄ is independently selected from the group consisting of hydrido,hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R₉ and R₁₃ to form a ringselected from the group consisting of a cycloalkenyl ring having from 5through 8 contiguous members and a heterocyclyl ring having from 5through 8 contiguous members, and a spacer selected from a moiety havinga chain length of 2 to 5 atoms connected to the point of bondingselected from the group consisting of R₄ and R₈ to form a heterocyclylhaving from 5 through 8 contiguous members with the proviso that, when Yis a covalent bond, an R₁₄ substituent is not attached to Y;

R₁₄ and R₁₅ can be taken together to form a spacer selected from amoiety having a chain length of 2 to 5 atoms to form a heterocyclyl ringhaving from 5 through 8 contiguous members;

R₁₄ and R₁₉ can be taken together to form a spacer selected from amoiety having a chain length of 2 to 5 atoms to form a heterocyclyl ringhaving from 5 through 8 contiguous members;

R₁₄ and R₁₄, when bonded to the different atoms, can be taken togetherto form a group selected from the group consisting of a covalent bond,alkylene, haloalkylene, and a spacer selected from a group consisting ofa moiety having a chain length of 2 to 5 atoms connected to form a ringselected from the group of a saturated cycloalkyl having from 5 through8 contiguous members, a cycloalkenyl having from 5 through 8 contiguousmembers, and a heterocyclyl having from 5 through 8 contiguous members;

R₁₄ and R₁₄, when bonded to the same atom can be taken together to forma group selected from the group consisting of oxo, thiono, alkylene,haloalkylene, and a spacer selected from the group consisting of amoiety having a chain length of 3 to 7 atoms connected to form a ringselected from the group consisting of a cycloalkyl having from 4 through8 contiguous members, a cycloalkenyl having from 4 through 8 contiguousmembers, and a heterocyclyl having from 4 through 8 contiguous members;

W is selected from the group consisting of O, C(O), C(S), C(O)N(R₁₄),C(S)N(R₁₄), (R₁₄)NC(O), (R₁₄)NC(S), S, (O), S(O)₂, S(O)₂N(R₁₄),(R₁₄)NS(O)₂, and N(R₁₄) with the proviso that R₁₄ is selected from otherthan halo and cyano;

Z is independently selected from a group consisting of a covalent singlebond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 4,(CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 2 with the proviso that, when Z is a covalentsingle bond, an R₁₅ substituent is not attached to Z;

R₁₅ is independently selected, when Z is (C(R₁₅)₂)_(q) wherein q is aninteger selected from 1 through 4, from the group consisting of hydrido,hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R₄ and R₈ to form a ringselected from the group consisting of a cycloalkenyl ring having from 5through 8 contiguous members and a heterocyclyl ring having from 5through 8 contiguous members, and a spacer selected from a moiety havinga chain length of 2 to 5 atoms connected to the point of bondingselected from the group consisting of R₉ and R₁₃ to form a heterocyclylhaving from 5 through 8 contiguous members;

R₁₅ and R₁₉ can be taken together to form a spacer selected from thegroup consisting of a covalent single bond and a linear moiety having achain length of 2 to 5 atoms to form a heterocyclyl ring having from 5through 8 contiguous members;

R₁₅ and R₁₅, when bonded to the different atoms, can be taken togetherto form a group selected from the group consisting of a covalent bond,alkylene, haloalkylene, and a spacer selected from a group consisting ofa moiety having a chain length of 2 to 5 atoms connected to form a ringselected from the group of a saturated cycloalkyl having from 5 through8 contiguous members, a cycloalkenyl having from 5 through 8 contiguousmembers, and a heterocyclyl having from 5 through 8 contiguous members;

R₁₅ and R₁₅, when bonded to the same atom can be taken together to forma group selected from the group consisting of oxo, thiono, alkylene,haloalkylene, and a spacer selected from the group consisting of amoiety having a chain length of 3 to 7 atoms connected to form a ringselected from the group consisting of a cycloalkyl having from 4 through8 contiguous members, a cycloalkenyl having from 4 through 8 contiguousmembers, and a heterocyclyl having from 4 through 8 contiguous members;

R₁₅ is independently selected, when Z is (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k)wherein j and k are integers independently selected from 0 through 2,from the group consisting of hydrido, halo, cyano, aryloxy, carboxyl,acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido,alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma linear moiety having a chain length of 3 to 6 atoms connected to thepoint of bonding selected from the group consisting of R₄ and R₈ to forma ring selected from the group consisting of a cycloalkenyl ring havingfrom 5 through 8 contiguous members and a heterocyclyl ring having from5 through 8 contiguous members, and a spacer selected from a linearmoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R₉ and R₁₃ to form aheterocyclyl ring having from 5 through 8 contiguous members;

R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are independentlyselected from the group consisting of perhaloaryloxy, alkanoylalkyl,alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido,N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl,cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that there are one to fivenon-hydrido ring substituents R₄, R₅, R₆, R₇, and R₈ present, that thereare one to five non-hydrido ring substituents R₉, R₁₀, R₁₁, R₁₂, and R₁₃present, and R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are eachindependently selected to maintain the tetravalent nature of carbon,trivalent nature of nitrogen, the divalent nature of sulfur, and thedivalent nature of oxygen;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁and R₁₂, and R₁₂ and R₁₃ can be independently selected to form spacerpairs wherein a spacer pair is taken together to form a linear moietyhaving from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇and R₈, can be used at the same time and that no more than one of thegroup consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂,and R₁₂ and R₁₃ can be used at the same time;

R₄ and R₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ can be independentlyselected to form a spacer pair wherein said spacer pair is takentogether to form a linear moiety wherein said linear moiety forms a ringselected from the group consisting of a partially saturated heterocyclylring having from 5 through 8 contiguous members and a heteroaryl ringhaving from 5 through 6 contiguous members with the proviso that no morethan one of the group consisting of spacer pairs R₄ and R₉, R₄ and R₁₃,R₈ and R₉, and R₈ and R₁₃ can be used at the same time;

R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀, and R₇ and R₁₂ can be independentlyselected to form a spacer pair wherein said spacer pair is takentogether to form a linear moiety wherein said linear moiety forms a C8to C13 heterocyclyl ring having from 8 through 13 contiguous memberswith the proviso that no more than one of the group consisting of spacerpairs R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀, and R₇ and R₁₂ can be used atthe same time;

R₁₉ is selected from the group consisting of hydrido, hydroxyalkyl,acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkanoyl,heteroarylthio, aralkylthio, aroyl, heteroaroyl, aralkoxyalkyl,alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl,heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl,diaralkoxyphosphonoalkyl, and a spacer group selected from the groupconsisting of a covalent single bond and a linear moiety having a chainlength of 2 to 5 atoms connected to a point of bonding selected from thegroup consisting of R₄, R₈, R₉, and R₁₃ to form a heterocyclyl ringhaving from 5 through 8 contiguous members.

In another embodiment, the compounds correspond to Formula V-H wherein mis an integer selected from 0 through 5; n is an integer selected from 0through 5; the sum of m plus n is an integer selected from 0 through 6;D₁, D₂, D₃, D₄, J₁, J₂, J₃, J₄, K₁, and K₂ are each a carbon atom; and aterminal carbon atom of the CH(R₃) moiety is directly connected by acovalent single bond to the nitrogen when m=0. Compounds of Formula V-Hwherein m is an integer selected from 0 through 5, n is an integerselected from 0 through 5, the sum of m plus n is an integer selectedfrom 0 through 6, and D₁, D₂, D₃, D₄, J₁, J₂, J₃, J₄, K₁, and K₂ areeach a carbon atom, have the CH(R₃) moiety directly connected by acovalent single bond to the nitrogen when m=0 and correspond to FormulaV (also referred to herein as generic phenyl tertiaryomegaheteroalkylamines):

or a pharmaceutically acceptable salt thereof, wherein;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R₁₉, X, Y, and Z are as defined for the compounds of Formula V-H;

D₁, D₂, D₃, D₄, J₁, J₂, J₃, J₄, K₁, and K₂ are each carbon;

R₁₆ and R₄, R₁₆ and R₈, R₁₆ and R₉, R₁₆ and R₁₃, R₂ and R₃, R₉ and R₁₄,R₁₃ and R₁₄, R₄ and R₁₄, R₈ and R₁₄, R₁₄ and R₁₄, R₄ and R₁₅, R₈ andR₁₅, R₉ and R₁₅, R₁₃ and R₁₅, R₁₅ and R₁₅, R₄ and R₅, R₅ and R₆, R₆ andR₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, R₁₂ and R₁₃, R₄ andR₉, R₄ and R₁₃, R₈ and R₉, R₈ and R₁₃, R₁₆ and R₁₄, R₁₆ and R₁₅, R₂ andR₁₄, R₂ and R₁₅, R₂ and R₁₉, R₂ and R₄, R₂ and R₈, R₂ and R₉, R₂ andR₁₃, R₃ and R₁₄, R₃ and R₁₅, R₃ and R₁₉, R₃ and R₄,R₃and R₈, R₃ and R₉,R₃ and R₁₃, R₁₄ and R₁₉, R₁₄ and R₁₅, R₁₅ and R₁₉, R₅ and R₁₀, R₅ andR₁₂, R₇ and R₁₀, and R₇ and R₁₂ spacer pairs are as defined for thecompounds of Formula V-H.

In another embodiment, the compounds correspond to Formula V-H wherein mis an integer selected from 0 through 5; n is an integer selected from 0through 5; the sum of m plus n is an integer selected from 0 through 6;and a terminal carbon atom of the CH(R₃) moiety is directly connected bya covalent single bond to the nitrogen when m=0. Compounds of FormulaV-H wherein m is the integer zero, and n is an integer selected from 0through 5, have the CH(R₃) moiety directly connected by a covalentsingle bond to the nitrogen when m=0 and correspond to Formula VII-H(also referred to herein as generic substituted polycyclic heteroaryltertiary 2-heteroalkylamines):

or a pharmaceutically acceptable salt thereof, wherein;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,D₁, D₂, D₃, D₄, J₁, J₂, J₃, J₄, K₁, K₂, X, Y, and Z are as defined forthe compounds of Formula V-H;

R₁₆ and R₄, R₁₆ and R₈, R₁₆ and R₉, R₁₆ and R₁₃, R₂ and R₃, R₉ and R₁₄,R₁₃ and R₁₄, R₄ and R₁₄, R₈ and R₁₄, R₁₄ and R₁₄, R₄ and R₁₅, R₈ andR₁₅, R₉ and R₁₅, R₁₃ and R₁₅, R₁₅ and R₁₅, R₄ and R₅, R₅ and R₆, R₆ andR₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, R₁₂ and R₁₃, R₄ andR₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ spacer pairs are as definedfor the compounds of Formula V-H;

R₁₉ and spacer pairs R₁₆ and R₁₄, R₁₆ and R₁₅, R₂ and R₁₄, R₂ and R₁₅,R₂ and R₁₉, R₂ and R₄, R₂ and R₈, R₂ and R₉, R₂ and R₁₃, R₃ and R₁₄, R₃and R₁₅, R₃ and R₁₉, R₃ and R₄, R₃ and R₈, R₃ and R₉, R₃ and R₁₃, R₁₄and R₁₉, R₁₄ and R₁₅, R₁₅ and R₁₉, R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀,and R₇ and R₁₂ are not present.

In another embodiment of compounds of Formula VII-H,

D₁, D₂, J₁, J₂ and K₁ are each carbon with the proviso that at least oneof D₃, D₄, J₃, J₄ and K₂ is selected from the group consisting of O, S,and N, wherein D₃, D₄, J₃, J₄ and K₂ are independently selected from thegroup consisting of C, N, O, S and covalent bond with the provisos thatno more than one of D₃, D₄, J₃, J₄ and K₂ can be a covalent bond, nomore than one of D₃, D₄, J₃, J₄ and K₂ can be O, no more than one of D₃,D₄, J₃, J₄ and K₂ can be S, one of D₃, D₄, J₃, J₄ and K₂ must be acovalent bond when two of D₃, D₄, J₃, J₄ and K₂ are O and S, and no morethan four of D₃, D₄, J₃, J₄ and K₂ can be N;

D₁, D₂, J₁, J₂ and K₁ can be selected from the group consisting of C, O,S, N and covalent bond with the provisos that D₃, D₄, J₃, J₄ and K₂ areeach carbon and at least one of D₁, D₂, J₁, J₂ and K₁ is selected fromthe group consisting of O, S, and N wherein, when D₁, D₂, J₁, J₂ and K₁are selected from the group consisting of C, O, S, covalent bond, and N,no more than one of D₁, D₂, J₁, J₂ and K₁ can be a covalent bond, nomore than one of D₁, D₂, J₁, J₂ and K₁ can be O, no more than one of D₁,D₂, J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂ and K₁ must be acovalent bond when two of D₁, D₂, J₁, J₂ and K₁ are O and S, and no morethan four of D₁, D₂, J₁, J₂ and K₁ can be N;

n is an integer selected from 1 through 4;

X is oxy;

R₁₆ is selected from the group consisting of hydrido, acyl, aroyl, andtrialkylsilyl;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl,haloalkoxyalkyl, and haloalkenyloxyalkyl;

R₂ is selected from the group consisting of hydrido, hydroxy, aryl,aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl,halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, andcarboalkoxycyanoalkyl;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano,aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl,alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, andcarboxamidoalkyl;

Y is selected from the group consisting of covalent single bond and(C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond,(C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and(CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 2;

W is oxy;

R₁₅ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido, halo, haloalkyl, and alkyl

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy,alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio,hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy,alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl,N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido,N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy,heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy,alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro,lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio,arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl,arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio,alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo,haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl,aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy,heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboxamido, carboxamidoalkyl, and cyano;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁and R₁₂, and R₁₂ and R₁₃ spacer pairs can be independently selected fromthe group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene,diacyl, haloalkylene, and aryloxylene with the provisos that no morethan one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆,R₆and R₇, and R₇ and R₈ can be used at the same time and that no morethan one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ andR₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In a more specific embodiment of compounds of Formula VII-H,

D₁, D₂, J₁, J₂ and K₁ are each carbon;

D₃, D₄, J₃, J₄ and K₂ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that atleast one of D₃, D₄, J₃, J₄ and K₂ is selected from the group consistingof O, S, and N, wherein no more than one of D₃, D₄, J₃, J₄ and K₂ can bea covalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ can be O, nomore than one of D₃, D₄, J₃, J₄ and K₂ can be S, one of D₃, D₄, J₃, J₄and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are Oand S, and no more than four of D₃, D₄, J₃, J₄ and K₂ can be N;

n is an integer selected from 1 through 3;

X is oxy;

R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₁₆ is selected from the group consisting of acetyl, benzoyl, dimethyltert-butylsilyl, hydrido, and trimethylsilyl;

R₂ is selected from the group consisting of hydrido, hydroxy, methyl,ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl,trifluoromethyl, 4trifluoromethylphenyl,1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl,and pentafluorophenoxymethyl;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano,acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl,methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, andpentafluorophenoxymethyl.

In a more specific embodiment of compounds of Formula VII-H,

D₃, D₄, J₃, J₄ and K₂ are each carbon;

D₁, D₂, J₁, J₂ and K₁ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that atleast one of D₁, D₂, J₁, J₂ and K₁ is selected from the group consistingof O, S, and N, wherein no more than one of D₁, D₂, J₁, J₂ and K₁ can bea covalent bond, no more than one of D₁, D₂, J₁, J₂ and K₁ can be O, nomore than one of D₁, D₂, J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂and K₁ must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are Oand S, and no more than four of D₁, D₂, J₁, J₂ and K₁ can be N;

n is an integer selected from 1 through 3;

X is oxy;

R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₁₆ is selected from the group consisting of acetyl, benzoyl, dimethyltert-butylsilyl, hydrido, and trimethylsilyl;

R₂ is selected from the group consisting of hydrido, hydroxy, methyl,ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl,trifluoromethyl, trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl,chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl,chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, andheptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano,acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl,methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, andpentafluorophenoxymethyl.

In a preferred embodiment of compounds of Formula VII-H, the compoundscorrespond to the Formula VII (also referred to herein as generic phenyltertiary 2-heteroalkylamines):

or a pharmacuetically acceptable salt thereof, wherein;

n is an integer selected from 0 through 4;

X is selected from the group consisting of O, H, F, S, S(O), NH, N(OH),N(alkyl), and N(alkoxy);

R₁₆ is selected from the group consisting of hydrido, alkyl, acyl,aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from the groupconsisting of a covalent single bond and a linear spacer moiety having achain length of 1 to 4 atoms linked to the point of bonding of anyaromatic substituent selected from the group consisting of R₄, R₈, R₉,and R₁₃ to form a heterocyclyl ring having from 5 through 10 contiguousmembers with the proviso that said linear spacer moiety is other thancovalent single bond when R₂ is alkyl;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl,haloalkoxyalkyl, and haloalkenyloxyalkyl;

R₂ is selected from the group consisting of hydrido, hydroxy,hydroxyalkyl, aryl, aralkyl, alkyl, alkenyl, aralkoxyalkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, monocyanoalkyl, and dicyanoalkyl,carboalkoxycyanoalkyl;

R₃ is selected from the group consisting of hydrido, hydroxy, halo,cyano, hydroxyalkyl, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl,alkoxyalkyl, aroyl, heteroaroyl, alkenyloxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboxamide, and carboxamidoalkyl;

Y is selected from the group consisting of covalent single bond and(C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, hydroxy, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond,C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and(CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 2;

W is selected from the group consisting of O, C(O), C(S), C(O)N(R₁₄),C(S)N(R₁₄), (R₁₄)NC(O), (R₁₄)NC(S), S, S(O), S(O)₂, S(O)₂N(R₁₄),(R₁₄)NS(O)₂, and N(R₁₄) with the proviso that R₁₄ is other than cyano;

R₁₅ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy,alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio,hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy,alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl,N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido,N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy,heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl,heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido,alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl,carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁and R₁₂, and R₁₂ and R₁₃ can be independently selected to form spacerpairs wherein a spacer pair is taken together to form a linear moietyhaving from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R₄ and R₅, R₅ and R₆ and R₇, and R₇ andR₈, can be used at the same time and that no more than one of the groupconsisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂and R₁₃ can be used at the same time.

In a preferred embodiment of compounds of Formula VII, compounds havethe Formula VII-2:

wherein;

n is an integer selected from 1 through 4;

R₁₆ is selected from the group consisting of hydrido, acyl, aroyl, andtrialkylsilyl;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl,haloalkoxyalkyl, and haloalkenyloxyalkyl;

R₂ is selected from the group consisting of hydrido, hydroxy, aryl,aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl,halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, andcarboalkoxycyanoalkyl;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano,aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl,alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, andcarboxamidoalkyl;

Y is selected from the group consisting of covalent single bond and(C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond,(C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and(CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 2;

W is oxy;

R₁₅ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido, halo, haloalkyl, and alkyl

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy,alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio,hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy,alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl,N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido,N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy,heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy,alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro,lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio,arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl,arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio,alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo,haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl,aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy,heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamindo, carboalkoxyalkyl, carboalkoxyalkenyl,carboxamido, carboxamidoalkyl, and cyano;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁and R₁₂, and R₁₂ and R₁₃ spacer pairs can be independently selected fromthe group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene,diacyl, haloalkylene, and aryloxylene with the provisos that no morethan one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆,R₆ and R₇, and R₇ and R₈ can be used at the same time and that no morethan one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ andR₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In a more preferred embodiment of compounds of Formula VII-2,

n is an integer selected from 1 through 2;

R₁ is selected from the group consisting of haloalkyl andhaloalkoxyalkyl;

R₁₆ is hydrido;

R₂ is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;

R₃ is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, and haloalkoxyalkyl;

Y is selected from the group consisting of a covalent single bond andalkylene;

Z is selected from the group consisting of a covalent single bond andalkylene;

R₁₄ is selected from the group consisting of hydrido, alkyl, andhaloalkyl;

R₁₅ is selected from the group consisting of hydrido, alkyl, andhaloalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido and halo;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy,heterocyclylcarbonyl, hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl,alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy,heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio,hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl,heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.

In an even more preferred embodiment of compounds of Formula VII-2,

n is the integer 1;

R₁₆ is hydrido;

R₁ is haloalkyl;

R₂ is selected from the group consisting of hydrido, alkyl, haloalkyl,aryl, and haloalkoxy;

R₃ is selected from the group consisting of hydrido, alkyl, andhaloalkyl;

Y is alkylene;

Z is covalent single bond;

R₁₄ is hydrido;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido and halo;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl,cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, alkyl,halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio,aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl,cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl,cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, andheteroaryloxyalkyl.

In an embodiment of compounds of Formula VII-2,

n is an integer selected from 1 to 3;

R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₁₆ is selected from the group consisting of acetyl, benzoyl, dimethyltert-butylsilyl, hydrido, and trimethylsilyl;

R₂ is selected from the group consisting of hydrido, hydroxy, methyl,ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl,trifluoromethyl, 4-trifluoromethylphenyl,1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl,and pentafluorophenoxymethyl;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano,acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl,methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, andpentafluorophenoxymethyl.

In a preferred embodiment of compounds of Formula VII-2,

n is the integer 1;

R₁₆ is hydrido;

R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl;

R₂ is selected from the group consisting of hydrido, methyl, ethyl,propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, andheptafluoropropyl;

R₃ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, ethyl, vinyl, methoxymethyl,trifluoromethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl.

In a even more preferred embodiment of compounds of Formula VII-2,

n is the integer 1;

R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl;

R₁₆ is hydrido;

R₂ is selected from the group consisting of hydrido, methyl, ethyl,phenyl, 4-trifluoromethylphenyl, trifluoromethyl,trifluoromethoxymethyl, 1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl,chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, andheptafluoropropyl;

R₃ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, andchlorodifluoromethyl;

In a most preferred embodiment of compounds of Formula VII-2,

n is the integer 1;

R₁ is selected from the group consisting of trifluoromethyl andpentafluoroethyl;

R₁₆ is hydrido;

R₂ is selected from the group consisting of hydrido, phenyl, andtrifluoromethyl;

R₃ is selected from the group consisting of hydrido, methyl,trifluoromethyl, and difluoromethyl;

In another embodiment of compounds of Formula VII, compounds have theFormula Cyclo-VII:

wherein:

R₁₆ is taken together with R₄, R₈, R₉ or R₁₃ to form a spacer selectedfrom the group consisting of a covalent single bond and a linear spacermoiety having a chain length of 1 to 4 atoms to form a heterocyclyl ringhaving from 5 through 10 contiguous members with the proviso that saidlinear spacer moiety is other than covalent single bond when R₂ isalkyl;

n is an integer selected from 1 through 3;

X is selected from the group consisting of O, S, NH, N(alkyl), andN(alkoxy);

R₁ is selected from the group consisting of haloalkyl, haloalkenyl,haloalkoxyalkyl, and haloalkenyloxyalkyl;

R₂ is selected from the group consisting of hydrido, hydroxy,hydroxyalkyl, aryl, aralkyl, alkyl, alkenyl, aralkoxyalkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, monocyanoalkyl, and dicyanoalkyl,carboalkoxycyanoalkyl;

R₃ is selected from the group consisting of hydrido, hydroxy, halo,cyano, hydroxyalkyl, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl,alkoxyalkyl, aroyl, heteroaroyl, alkenyloxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboxamide, and carboxamidoalkyl;

Y is selected from the group consisting of covalent single bond and(C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, hydroxy, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond,(C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and(CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 2;

W is selected from the group consisting of O, C(O), S, S(O), and S(O)₂;

R₁₅ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ can be independently selected from the groupconsisting of hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy,alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio,hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy,alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl,N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido,N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy,heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl,heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido,alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl,carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl;

R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂,and R₁₂ and R₁₃ can be independently selected to form spacer pairswherein a spacer pair is taken together to form a linear moiety havingfrom 3 through 6 contiguous atoms connecting the points of bonding ofsaid spacer pair members to form a ring selected from the groupconsisting of a cycloalkenyl ring having 5 through 8 contiguous members,a partially saturated heterocyclyl ring having 5 through 8 contiguousmembers, a heteroaryl ring having 5 through 6 contiguous members, and anaryl with the provisos that no more than one of the group consisting ofspacer pairs R₅ and R₆, R₆ and R₇, and R₇ and R₈, can be used at thesame time and that no more than one of the group consisting of spacerpairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be usedat the same time.

In an embodiment of compounds of Formula Cyclo-VII,

n is the integer 1;

X is selected from the group consisting of O, NH, and S;

R₁₆ is taken together with R₄, R₈, R₉ or R₁₃ to form a spacer selectedfrom the group consisting of a covalent single bond, CH₂, CH(CH₃), CF₂,C(O), C(S), and SO₂;

R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl;

R₂ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, vinyl, trifluoromethyl, pentafluoroethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, 2,2,3,3,3-pentafluoropropyl, andheptafluoropropyl;

R₃ is selected from the group consisting of hydrido, methyl, ethyl,vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl, trifluoromethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl.

In another embodiment of compounds of Formula Cyclo-VII, compounds havethe formula:

n is the integer 1;

X is oxy;

R₁₆ and R₄ are taken together to form a covalent single bond;

R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl;

R₂ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, vinyl, trifluoromethyl, pentafluoroethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, 2,2,3,3,3-pentafluoropropyl, andheptafluoropropyl;

R₃ is selected from the group consisting of hydrido, methyl, ethyl,vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl, trifluoromethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl.

In another embodiment of compounds of Formula VII, compounds have theFormula VII-3:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is selected from the group consisting of haloalkyl, haloalkenyl,haloalkoxyalkyl and haloalkenyloxyalkyl;

R₂ is hydroxyalkyl;

Y is selected from the group consisting of covalent single bond and(C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond,(C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and(CH(₁₅))_(j)—W—(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 2;

W is oxy;

R₁₅ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido, halo, haloalkyl, and alkyl

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy,alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio,hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy,alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl,N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido,N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy,heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy,alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro,lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio,arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl,arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio,alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo,haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl,aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy,heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboxamido, carboxamidoalkyl, and cyano;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁and R₁₂, and R₁₂ and R₁₃ spacer pairs can be independently selected fromthe group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene,diacyl, haloalkylene, and aryldioxylene with the provisos that no morethan one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆,R₆ and R₇, and R₇ and R₈ can be used at the same time and that no morethan one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ andR₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In an embodiment of compounds of Formula VII-3,

R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, andpentafluorophenoxymethyl;

R₂ is hydroxymethyl, 1-hydroxyethyl, and 1,2-dihydroxyethyl.

In another embodiment of compounds of Formula VII, compounds have theFormula VII4:

wherein;

X is oxy;

R₁ is selected from the group consisting of haloalkyl andhaloalkoxyalkyl;

R₁₆ is hydrido;

R₂ and R₃ are taken together to form a linear spacer moiety selectedfrom the group consisting of a covalent single bond and a moiety havingfrom 1 through 6 contiguous atoms to form a ring selected from the groupconsisting of a cycloalkyl having from 3 through 8 contiguous members, acycloalkenyl having from 5 through 8 contiguous members, and aheterocyclyl having from 4 through 8 contiguous members;

Y is selected from the group consisting of a covalent single bond andalkylene;

Z is selected from the group consisting of a covalent single bond andalkylene;

R₁₄ is selected from the group consisting of hydrido, alkyl, andhaloalkyl;

R₁₅ is selected from the group consisting of hydrido, alkyl, andhaloalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido and halo;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy,heterocyclylcarbonyl, hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl,alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy,heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio,hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl,heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.

In an embodiment of compounds of Formula VII-4,

X is oxy;

R₁₆ is hydrido;

R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl;

R₂ and R₃ spacer pair is selected from the group consisting of—CH₂SCH₂—, —CH₂OCH₂—, —CH₂CH(R₁₇)—, —CH═C(R₁₇)—, —CH₂S(O)₂CH₂—,—CH₂CH₂CH(R₁₇)—, —CH₂CH(R₁₇)CH₂—, —CH₂CH═C(R₁₇)—, —CH(R₁₇)CH═CH—,—CH₂C(R₁₇)═CH—, —CH(R₁₇)C(O)N(R₁₇)—, —C(O)N(R₁₇)CH(R₁₇)—,—CH(R₁₇)C(O)NHCH₂—, —CH₂C(O)NHCH(R₁₇)—, —CH(R₁₇)CH(R₁₇)C(O)NH—,—C(O)NHCH(R₁₇)CH(R₁₇)—, —CH₂CH(R₁₇)CH₂CH₂—, —CH(R₁₇)CH₂CH₂CH₂—,—CH₂CH═CHCH₂—, —CH═CHCH₂CH₂—, —CH═CHCH═CH—, —CH₂CH₂CH₂CH₂CH₂—,—CH₂CH₂CH═CHCH₂—, —(CH₂)₂O—, —(CH₂CHR₁₇)O—, —(CF₂)₂O—, —SCH₂CH₂—,—S(O)CH₂CH₂—, —CH₂S(O)CH₂—, —CH₂S(O)CH₂CH₂—, —S(O)₂CH₂—, —CH₂N(R₁₇)O—,—CH₂CH₂C(O)—, —CH₂C(O)NR₁₇—, and —CH₂NR₁₇CH₂— wherein R₁₇ is selectedfrom the group consisting of H, CH₃, OCH₃, CF₃, CH₂CH₃, F, Cl, CH₂OH,and OH.

In an embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3,VII-4, and Cyclo-VII,

Y is selected from the group consisting of a covalent single bond,methylene, 2-fluoroethylidene, ethylidene, 2,2-difluoroethylidene, and2,2,2-trifluoroethylidene;

Z is group selected from the group consisting of covalent single bond,oxy, methyleneoxy, methylene, ethylene, ethylidene, 2-fluoroethylidene,2,2-difluoroethylidene, and 2,2,2-trifluoroethylidene;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido and fluoro;

R₅ and R₁₀ are independently selected from the group consisting ofacetoxy, 3-acetamidophenoxy, 3-acetylphenoxy, 4-acetylphenyIsulfonyl,amino, 4-acetylphenylthio, acetylthio,3-aminobenzyloxy,4-aminobenzyloxy, 4-aminophenoxy, 3-aminophenyl, benzoyl, benzoylamido,benzoylmethoxy, benzyl, N-benzylamidocarbonyl, benzylamino,3-benzylimidazolylmethoxy, N-benzyl-N-methylamidocarbonyl, benzyloxy,4-benzyloxybenzyloxy, 4-benzylphenoxy, 4-benzylpiperidinyl, bromo,5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, bromomethyl,4-bromo-2-nitrophenoxy, 2-bromobenzyloxy, 3-bromobenzyloxy,4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy,4-bromothiophen-3-ylthio, butoxy, 4-butoxyphenoxy,N-butylylcarboxamnido, N-butyl-N-methylcarboxamido,N-butyl-4-ethoxycarbonylphenylamino, 4-butylphenoxy, carboxy,carboxamidomethoxy, 3-carboxybenzyloxy, 4-carboxybenzyloxy,4-carboxyphenyl, 5-carboxypyrid-3-yloxy, chloro, 3-chlorobenzyl,2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy,2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy,3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl,3-chloro-2-fluorobenzyloxy, 3-chloro-2-hydroxypropoxy,4-chloro-3-methylphenoxy, 4-chloro-3-methylbenzyl,2-chloro-4-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy,3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy,4-chloro-3-fluorophenoxy, 4-chloro-2-fluorophenoxy,3-chloro-4-fluorophenylsulfonylamido, 4-chlorophenyl,3-chlorophenylamino, 4-chlorophenylamino,5-chlorophenylthiophen-3-ylmethoxy, 5-chloropyrid-3-yloxy,4-chlorothiophen-2-ylmethylthio, cyano, 3-cyanobenzyloxy,4-cyanobenzyloxy, 4-(2-cyano-2-ethoxycarbonylacetyl)phenylamino,N-(2-cyanoethyl)-4-methylphenylamino, 2-cyanopyrid-3-yloxy,4-cyanophenoxy, 4-cyanophenyl, 3-cyanophenylamino, 4-cyanophenylamino,3-cyanopropoxy, cyclobutoxy, cyclobutyl, cyclohexylamidocarbonyl,cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl,N-cyclopentylamidocarbonyl, cyclopentylcarbonyl, 4-cyclopentylphenxoy,cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 3,5-dichlorobenzyloxy,3,5-dichloro-4-methylphenoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy,3,5-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl,3,5-dichloro-4-methoxyphenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-dichlorophenyl, 3,4-difluorophenoxy, 2,4-difluorobenzyloxy,2,5-difluorobenzyloxy, 3,5-difluorobenzyloxy, 2,6-difluorobenzyloxy,3,5-difluorophenoxy, 3,4-difluorophenyl, 4-difluoromethoxybenzyloxy,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,3-difluorobenzyloxy,3,4-difluorobenzyloxy, difluoromethoxy, 2,5-difluorophenoxy,3,5-difluorophenylamino, 3,5-dimethoxyphenoxy, dimethylamino,N,N-dimethylcarboxamido, 2-(N,N-dimethylamino)ethoxy,3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy,3,5-dimethylphenoxy, 3,4-dimethylphenoxy,3,5-dimethyl-4-(N,N-dimethylamino)phenyl, 3,4-dimethoxyphenylamnino,3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 1,1-dimethylhydroxymethyl,3,3-dimethyl-2-oxobutoxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl,1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, ethoxycarbonyl,3-ethoxycarbonylphenylamino, 4-ethoxycarbonylphenylamino,1-ethoxycarbonylbutoxy, 4-ethoxyphenoxy, ethyl,4,4-ethylenedioxypiperidinyl, N-ethyl-N-methylcarboxamido,3-ethylphenoxy, 4-ethylaminophenoxy, 4-ethylbenzyloxy,3-ethyl-5-methylphenoxy, N-ethyl-3-methylphenylamino,N-ethyl-4-methoxyphenylamino, fluoro, 4-fluorobenzylamino,4-fluoro-3-methylbenzyl, 2-fluoro-3-methylbenzyloxy,4-fluoro-3-methylphenyl, 4-fluorobenzoyl, 4-fluoro-3-methylbenzoyl,3-fluorobenzyloxy, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy,3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy,2-fluoro-3-trifluoromethylbenzyloxy, 4-fluoro-2-trfluoromethylbenzyloxy,4-fluoro-3-trifluoromethylbenzyloxy,5-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamidocarbonylamido, 4-fluorophenylamino,4-fluorobenzoylamido, 4-fluorobenzylamidocarbonyl,2-fluoro-4-trifluoromethylphenoxy, 4-fluoro-2-trifluoromethylphenoxy,2-fluoro-4-chloromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl,N-(2,2,3,3,4,4,4-heptafluorobutyl)amidocarbonyl, heptafluoropropyl,1,1,1,3,3,3-hexafluoropropyl, hydrazinocarbonyl, hydrido, hydroxy,2-hydroxyethoxy, 1-hydroxyisobutyl, 3-hydroxy-2,2-dimethylpropoxy,hydroxymethyl, 3-hydroxymethylphenoxy, 4-hydroxyphenoxy,3-hydroxypropoxy, 2-hydroxy-3,3,3-trifluoropropoxy,4-imidazol-1-yl-phenoxy, indol-5-yloxy, iodo, 3-iodobenzyloxy,isobutylamino, isobutoxy, N-isobutoxycarbonylamido, isobutyl,isobutyryl, isobutyrylamido, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,isopropoxy, isopropyl, isopropylamidocarbonyl,isopropylamidocarbonylamido, 4-isopropylbenzyloxy,N-isopropyl-N-methylamino, 3-isopropylphenoxy, 4-isopropylphenoxy,isopropylthio, 4-isopropyl-3-methylphenoxy, isopropylsulfonyl,isopropylsulfonylamido, isoquinolin-3-yloxy, 3-isothiazolyl,4-isothiazolyl, 5-isothiazolyl, methoxy, 3-methoxybenzoylamido,3-methoxybenzyl, methoxycarbonyl, 4-methoxycarbonylbutoxy,3-methoxycarbonylbenzyloxy, 4-methoxycarbonylbenzyloxy, 2-methoxyethoxy,3-methoxycarbonylmethoxy, 3-methoxycarbonylprop-2-enyloxy,methoxymethyl, N-methoxy-N-methylcarboxamido, 3-methoxyphenoxy,4-methoxyphenoxy, 4-methoxy-3-methylphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino,3-methoxyphenylamidocarbonylamido, 4-methoxyphenylthio, methyl,N-methyl-4-methoxyphenylamino, 4-methylbenzyl, 3-methylbutyl,3-methylphenoxy, 4-methylsulfonylphenyl, 3-methyl-4-methylthiophenoxy,3-methylbenzyloxy, 4-methylbenzyloxy, 2-methyl-3-nitrophenoxy,2-methyl-5-nitrophenoxy, 4-methylphenoxy, 4-methylphenyl,N-methyl-N-phenylamidocarbonyl, N-methyl-N-propylcarboxamido,4-(5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl)phenylamino,3-methylphenylsulfonylamido, 4-methylpiperazin-1-ylcarbonyl,1-methylpropoxy, 3-methylbut-2-enyloxy, 2-methylpyrid-6-yl,3-methylpyrid-2-yl, 2-methylpyrid-3-yloxy, 2-methylpyrid-5-yloxy,N-methylpyrrol-2-yl, 4-methylsulfonylphenylsulfonyl,4-methylsulfonylphenylthio, 4-methylthiophenoxy, 4-methylthiophenyl,4-methylthiobenzyl, morpholin-4-ylcarbonyl, 2-naphthyloxy,N-neopentylamidocarbonyl, nitro, 3-nitrobenzyl, 3-nitrobenzyloxy,4-nitrobenzyloxy, 2-nitrophenoxy, 3-nitrophenoxy, 4-nitrophenoxy,3-nitrophenyl, 4-nitrophenylsulfonyl, 3-nitrophenylsulfonylamido,4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-oxobutoxy,5-oxohexoxy, N-oxypyrid-3-ylmethylsulfonyl,2,3,4,5,6-pentafluorobenzyloxy, pentafluoroethyl, pentafluoroethylthio,4-(2,3,4,5,6-pentafluorophenyl)-2,3,5,6-tetrafluorophenoxy,2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl,1,1,2,2,3-pentafluoropropyl, phenoxy, 3-phenoxybenzyloxy, phenyl,phenylamidocarbonylamido, 1-(N-phenylcarboxamido)ethoxy, phenylamino,4-phenylbenzyloxy, 1-phenylethoxy, phenylhydroxymethyl, 3-phenylphenoxy,4-phenylphenoxy, phenylsulfonyl, phenylsulfonylamido,2-phenylsulfonylethoxy, phenylthio, 1-piperidinyl,piperidin-4-ylcarbonyl, piperidin-4-ylsulfonyl, piperidin-4-ylthio,hexahydropyranyloxy, 4-propanoyl, 4-propanoylphenoxy, propoxy,4-propylphenoxy, 4-propylphenylamino, 4-propoxyphenoxy, pyrid-2-yl,pyrid-3-yl, pyrid-3-ylcarboxamido, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy,pyrid-4-ylmethoxy, pyrid-2-yloxy, pyrid-3-yloxy, pyrid-2-ylmethylthio,pyrid-4-ylthio, pyrimid-2-yl, pyrimid-2-yloxy, pyrimid-5-yloxy,pyrrolin-1-ylcarbonyl, 2-(pyrrolidin-1-yl)ethoxy, thiophen-3-yl,sec-butyl, 4-sec-butylphenoxy,tert-butoxy, N-tert-butylamidocarbonyl,4-tert-butylbenzyl, 4-tert-butylbenzyloxy, 3-tert-butylphenoxy,4-tert-butylphenoxy, 4-tert-butylphenyl, tetrazol-5-yl,3-(1,1,2,2-tetrafluoroethoxy)benzylamino, 1,1,2,2-tetrafluoroethoxy,2,3,5,6-tetrafluoro-4-methoxybenzyloxy,2,3,5,6-tetrafluoro-4-trifluoromethylbenzyloxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiol, 4-thiophenoxy, thiophen-2-yl,2,3,5-trifluorobenzyloxy, 2,4,6-trifluorobenzyloxy,N-(4,4,4-trifluorobutyl)-4-methoxyphenylamino, 2,2,2-trifluoroethoxy,2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl,N-(2,2,2-trifluoroethyl)amidocarbonyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 3-trifluoromethoxybenzylamidocarbonyl,3-trifluoromethoxybenzylamidocarbonylhydrazinocarbonyl,4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy,4-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenylamino,trifluoromethyl, 3-trifluoromethylbenzylamine,3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,2,4-bis-trifluoromethylbenzyloxy, 3,4-bis-trifluoromethylbenzyloxy,1,1-bis-trifluoromethyl-1-hydroxymethyl, 3,5-bis-trifluoromethylphenyl,3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy,4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,3-trifluoromethylphenylamidocarbonylamido, 4-trifluoromethylphenylamino,3-trifluoromethylphenylsulfonylamido, 3-trifluoromethylthiobenzyloxy,4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy,2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy,3,4,5-trimethoxyphenylamino, 3-trifluoromethylpyrid-2-yl,3-trifluoromethylpyrid-2-yloxy, 5-trifluoromethylpyrid-2-yloxy,3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy,3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, andtrifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting ofacetoxy, benzyloxy, bromo, butoxy, butoxycarbonyl, chloro,4-chlorophenyl, 3,4-dichlorophenoxy, cyano, 2-cyanophenyl,difluoromethoxy, ethoxy, fluoro, hydrido, hydroxy, methoxy,methoxycarbonyl, methyl, methylsulfonyl, morpholin-4-yl, nitro, octyl,phenoxy, phenyl, phenylethenyl, phenylethynyl, propoxy, thiophen-2-yl,trifluoromethyl, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, andtrifluoromethoxy;

R₇ and R₁₂ are independently selected from the group consisting ofbenzyloxy, hydrido, fluoro, hydroxy, methoxy, and trifluoromethyl;

R₅ and R₆ can be taken together to form a spacer group selected from thegroup consisting of benzylidene, 5-bromobenzylidene, ethylene-1,2-dioxy,tetrafluoroethylene-1,2-dioxy, 1,4-butadienyl, methylene-1,1-dioxy,phenoxylidene, and propylene-1,3-dioxy;

R₆ and R₇ can be taken together to form a spacer group selected from thegroup consisting of benzylidene, 5-bromobenzylidene, ethylene-1,2-dioxy,tetrafluoroethylene- 1,2-dioxy, 1,4-butadienyl, methylene-1,1-dioxy,phenoxylidene, and propylene-1,3-dioxy;

R₁₀ and R₁₁ can be taken together to form a spacer group selected fromthe group consisting of benzylidene, ethylene-1,2-dioxy,methylene-1,1-dioxy, phthaloyl, and tetrafluoroethylene-1,2-dioxy;

R₁₁ and R₁₂ can be taken together to form a spacer group selected fromthe group consisting of benzylidene, ethylene-1,2-dioxy,methylene-1,1-dioxy, phthaloyl, and tetrafluoroethylene-1,2-dioxy;

R₁₂ and R₁₃ can be the spacer group 1,4-butadienyl.

In a preferred embodiment of compounds of Formulas VII-H, VII, VII-2,VII-3, VII-4, and Cyclo-VII,

Y is selected from the group consisting of methylene, ethylene, andethylidene;

Z is covalent single bond;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido and fluoro;

R₅ and R₁₀ are independently selected from the group consisting of4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy,4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy,4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy,chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl,3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy,4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy,4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy,3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy,4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy,2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl,cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl,cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy,3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy,3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy,3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl,1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy,4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy,3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl,4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy,2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy,3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy,4-fluoro-2-trifluoromethylbenzyloxy,4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy,4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl,1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy,3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy,3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio,4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy,3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy,propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl,4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy,4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy,2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl,3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,2,4-bis-trifluoromethylbenzyloxy,1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl,3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy,3-trifluoromethylphenoxy, 3-trifluoromethylphenyl,3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy,2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, and trifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting ofchloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy,trifluoromethyl, and trifluoromethoxy;

R₇ and R₁₂ are independently selected from the group consisting ofhydrido, fluoro, and trifluoromethyl.

In an even more preferred embodiment of compounds of Formulas VII-H,VII, VII-2, VII-3, VII-4, and Cyclo-VII,

Y is methylene;

Z is covalent single bond;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido and fluoro;

R₅ and R₁₀ are independently selected from the group consisting ofbenzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy,2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy,3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy,3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino,5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy,cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy,difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy,4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl,4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy,3-fluorophenoxy, 3-fluoro-2-nitrophenoxy,2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl,3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl,2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl,4-isoxazolyI, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy,3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy,3-methylphenoxy, 3-methylmethylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy,thiophen-3-yl,tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy,1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy,2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl,3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy,4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy,3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, andtrifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting ofchloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy,and trifluoromethyl;

R₇ and R₁₂ are independently selected from the group consisting ofhydrido, fluoro, and trifluoromethyl.

In a most preferred embodiment of compounds of Formulas VII-H, VII,VII-2, VII-3, VII-4, and Cyclo-VII,

Y is methylene;

Z is covalent single bond;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consistingof hydrido and fluoro;

R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy,4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy,3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy,4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy,3-pentafluoroethylphenoxy, 3-tert-butylphenoxy,3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy),3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy,3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy;

R₁₀ is selected from the group consisting of cyclopentyl,1,1,2,2-tetrafluoroethoxy, 2-furyl,1,1-bis-trifluoromethyl-1-hydroxymethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethyl, and trifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting offluoro and hydrido;

R₇ and R₁₂ are independently selected from the group consisting ofhydrido and fluoro.

DEFINITIONS

The use of generic terms in the description of the compounds are hereindefined for clarity.

Standard single letter elemental symbols are used to represent specifictypes of atoms unless otherwise defined. The symbol “C” represents acarbon atom. The symbol “O” represents an oxygen atom. The symbol “N”represents a nitrogen atom. The symbol “P” represents a phosphorus atom.The symbol “S” represents a sulfur atom. The symbol “H” represents ahydrogen atom. Double letter elemental symbols are used as defined forthe elements of the periodical table (i.e., Cl represents chlorine, Serepresents selenium, etc.).

As utilized herein, the term “alkyl”, either alone or within other termssuch as “haloalkyl” and “alkylthio”, means an acyclic alkyl radicalcontaining from 1 to about 10, preferably from 1 to about 8 carbon atomsand more preferably 1 to about 6 carbon atoms. Said alkyl radicals maybe optionally substituted with groups as defined below. Examples of suchradicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl,oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl,tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.

The term “alkenyl” refers to an unsaturated, acyclic hydrocarbon radicalin so much as it contains at least one double bond. Such alkenylradicals contain from about 2 to about 10 carbon atoms, preferably fromabout 2 to about 8 carbon atoms and more preferably 2 to about 6 carbonatoms. Said alkenyl radicals may be optionally substituted with groupsas defined below. Examples of suitable alkenyl radicals includepropenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl,2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl,3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.

The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radicalin so much as it contains one or more triple bonds, such radicalscontaining about 2 to about 10 carbon atoms, preferably having fromabout 2 to about 8 carbon atoms and more preferably having 2 to about 6carbon atoms. Said alkynyl radicals may be optionally substituted withgroups as defined below. Examples of suitable alkynyl radicals includeethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl,pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl,hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.

The term “hydrido” denotes a single hydrogen atom (H). This hydridoradical may be attached, for example, to an oxygen atom to form a“hydroxyl” radical, one hydrido radical may be attached to a carbon atomto form a “methine” radical (═CH—), or two hydrido radicals may beattached to a carbon atom to form a “methylene” (—CH₂—) radical.

The term “carbon” radical denotes a carbon atom without any covalentbonds and capable of forming four covalent bonds.

The term “cyano” radical denotes a carbon radical having three of fourcovalent bonds shared by a nitrogen atom.

The term “hydroxyalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with a hydroxyl as defined above.Specifically embraced are monohydroxyalkyl, dihydroxyalkyl andpolyhydroxyalkyl radicals.

The term “alkanoyl” embraces radicals wherein one or more of theterminal alkyl carbon atoms are substituted with one or more carbonylradicals as defined below. Specifically embraced are monocarbonylalkyland dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicalsinclude formyl, acetyl, and pentanoyl. Examples of dicarbonylalkylradicals include oxalyl, malonyl, and succinyl.

The term “alkylene” radical denotes linear or branched radicals havingfrom 1 to about 10 carbon atoms and having attachment points for two ormore covalent bonds. Examples of such radicals are methylene, ethylene,ethylidene, methylethylene, and isopropylidene.

The term “alkenylene” radical denotes linear or branched radicals havingfrom 2 to about 10 carbon atoms, at least one double bond, and havingattachment points for two or more covalent bonds. Examples of suchradicals are 1,1-vinylidene (CH₂═C), 1,2-vinylidene (—CH═CH—), and1,4-butadienyl (—CH═CH—CH═CH—).

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either abromo, chloro or a fluoro atom within the radical. Dihalo radicals mayhave two or more of the same halo atoms or a combination of differenthalo radicals and polyhaloalkyl radicals may have more than two of thesame halo atoms or a combination of different halo radicals. Morepreferred haloalkyl radicals are “lower haloalkyl” radicals having oneto about six carbon atoms. Examples of such haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The term “hydroxyhaloalkyl” embraces radicals wherein any one or more ofthe haloalkyl carbon atoms is substituted with hydroxy as defined above.Examples of “hydroxyhaloalkyl” radicals include hexafluorohydoxypropyl.

The term “haloalkylene radical” denotes alkylene radicals wherein anyone or more of the alkylene carbon atoms is substituted with halo asdefined above. Dihalo alkylene radicals may have two or more of the samehalo atoms or a combination of different halo radicals andpolyhaloalkylene radicals may have more than two of the same halo atomsor a combination of different halo radicals. More preferred haloalkyleneradicals are “lower haloalkylene” radicals having one to about sixcarbon atoms. Examples of “haloalkylene” radicals includedifluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkylsubstituted monofluoromethylene, and aryl substitutedtrifluoromethylene.

The term “haloalkenyl” denotes linear or branched radicals having from 1to about 10 carbon atoms and having one or more double bonds wherein anyone or more of the alkenyl carbon atoms is substituted with halo asdefined above. Dihaloalkenyl radicals may have two or more of the samehalo atoms or a combination of different halo radicals andpolyhaloalkenyl radicals may have more than two of the same halo atomsor a combination of different halo radicals.

The terms “alkoxy” and “alkoxyalkyl” embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy radical. The term “alkoxyalkyl” alsoembraces alkyl radicals having one or more alkoxy radicals attached tothe alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylradicals. More preferred alkoxy radicals are “lower alkoxy” radicalshaving one to six carbon atoms. Examples of such radicals includemethoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls. The“alkoxy” radicals may be further substituted with one or more haloatoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” and“haloalkoxyalkyl” radicals. Examples of such haloalkoxy radicals includefluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy,trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, andfluoropropoxy. Examples of such haloalkoxyalkyl radicals includefluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl,difluoromethoxyethyl, and trifluoroethoxymethyl.

The terms “alkenyloxy” and “alkenyloxyalkyl” embrace linear or branchedoxy-containing radicals each having alkenyl portions of two to about tencarbon atoms, such as ethenyloxy or propenyloxy radical. The term“alkenyloxyalkyl” also embraces alkenyl radicals having one or morealkenyloxy radicals attached to the alkyl radical, that is, to formmonoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferredalkenyloxy radicals are “lower alkenyloxy” radicals having two to sixcarbon atoms. Examples of such radicals include ethenyloxy, propenyloxy,butenyloxy, and isopropenyloxy alkyls. The “alkenyloxy” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkenyloxy” radicals. Examples of suchradicals include trifluoroethenyloxy, fluoroethenyloxy,difluoroethenyhloxy, and fluoropropenyloxy.

The term “haloalkoxyalkyl” also embraces alkyl radicals having one ormore haloalkoxy radicals attached to the alkyl radical, that is, to formmonohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term“haloalkenyloxy” also embraces oxygen radicals having one or morehaloalkenyloxy radicals attached to the oxygen radical, that is, to formmonohaloalkenyloxy and dihaloalkenyloxy radicals. The term“haloalkenyloxyalkyl” also embraces alkyl radicals having one or morehaloalkenyloxy radicals attached to the alkyl radical, that is, to formmonohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.

The term “alkylenedioxy” radicals denotes alkylene radicals having atleast two oxygens bonded to a single alkylene group. Examples of“alkylenedioxy” radicals include methylenedioxy, ethylenedioxy,alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. Theterm “haloalkylenedioxy” radicals denotes haloalkylene radicals havingat least two oxy groups bonded to a single haloalkyl group. Examples of“haloalkylenedioxy” radicals include difluoromethylenedioxy,tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstitutedmonofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendant manner or may be fused. The term “fused”means that a second ring is present (ie, attached or formed) by havingtwo adjacent atoms in common (ie, shared) with the first ring. The term“fused” is equivalent to the term “condensed”. The term “aryl” embracesaromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indaneand biphenyl.

The term “perhaloaryl” embraces aromatic radicals such as phenyl,naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the arylradical is substituted with 3 or more halo radicals as defined below.

The term “heterocyclyl” embraces saturated, partially saturated andunsaturated heteroatom-containing ring-shaped radicals having from 5through 15 ring members selected from carbon, nitrogen, sulfur andoxygen, wherein at least one ring atom is a heteroatom. Heterocyclylradicals may contain one, two or three rings wherein such rings may beattached in a pendant manner or may be fused. Examples of saturatedheterocyclic radicals include saturated 3 to 6-membered heteromonocylicgroup containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partiallysaturated heterocyclyl radicals include dihydrothiophene, dihydropyran,dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclicradicals, also termed “heteroaryl” radicals, include unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturatedcondensed heterocyclic group containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.;unsaturated condensed heterocyclic group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl,etc.] and the like. The term also embraces radicals where heterocyclicradicals are fused with aryl radicals. Examples of such fused bicyclicradicals include benzofuran, benzothiophene, and the like. Said“heterocyclyl” group may have 1 to 3 substituents as defined below.Preferred heterocyclic radicals include five to twelve membered fused orunfused radicals. Non-limiting examples of heterocyclic radicals includepyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl,pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl,furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl,1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,benzo(b)thiophenyl, benzimidazoyl, quinolinyl, tetraazolyl, and thelike.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.“Alkylsulfonyl”, embraces alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. “Alkylsulfonylalkyl”, embracesalkylsulfonyl radicals attached to an alkyl radical, where alkyl isdefined as above. “Haloalkylsulfonyl”, embraces haloalkyl radicalsattached to a sulfonyl radical, where haloalkyl is defined as above.“Haloalkylsulfonylalkyl”, embraces haloalkylsulfonyl radicals attachedto an alkyl radical, where alkyl is defined as above. The term“aminosulfonyl” denotes an amino radical attached to a sulfonyl radical.

The term “sulfinyl”, whether used alone or linked to other terms such asalkylsulfinyl, denotes respectively divalent radicals —S(O)—.“Alkylsulfinyl”, embraces alkyl radicals attached to a sulfinyl radical,where alkyl is defined as above. “Alkylsulfinylalkyl”, embracesalkylsulfinyl radicals attached to an alkyl radical, where alkyl isdefined as above. “Haloalkylsulfinyl”, embraces haloalkyl radicalsattached to a sulfinyl radical, where haloalkyl is defined as above.“Haloalkylsulfinylalkyl”, embraces haloalkylsulfinyl radicals attachedto an alkyl radical, where alkyl is defined as above.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferablearalkyl radicals are “lower aralkyl” radicals having aryl radicalsattached to alkyl radicals having one to six carbon atoms. Examples ofsuch radicals include benzyl, diphenylmethyl, triphenylmethyl,phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl areinterchangeable.

The term “heteroaralkyl” embraces heteroaryl-substituted alkyl radicalswherein the heteroaralkyl radical may be additionally substituted withthree or more substituents as defined above for aralkyl radicals. Theterm “perhaloaralkyl” embraces aryl-substituted alkyl radicals whereinthe aralkyl radical is substituted with three or more halo radicals asdefined above.

The term “aralkylsulfinyl”, embraces aralkyl radicals attached to asulfinyl radical, where aralkyl is defined as above.“Aralkylsulfinylalkyl”, embraces aralkylsulfinyl radicals attached to analkyl radical, where alkyl is defined as above.

The term “aralkylsulfonyl”, embraces aralkyl radicals attached to asulfonyl radical, where aralkyl is defined as above.“Aralkylsulfonylalkyl”, embraces aralkylsulfonyl radicals attached to analkyl radical, where alkyl is defined as above.

The term “cycloalkyl” embraces radicals having three to ten carbonatoms. More preferred cycloalkyl radicals are “lower cycloalkyl”radicals having three to seven carbon atoms. Examples include radicalssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. The term “cycloalkylalkyl” embraces cycloalkyl-substitutedalkyl radicals. Preferable cycloalkylalkyl radicals are “lowercycloalkylalkyl” radicals having cycloalkyl radicals attached to alkylradicals having one to six carbon atoms. Examples of such radicalsinclude cyclohexylhexyl. The term “cycloalkenyl” embraces radicalshaving three to ten carbon atoms and one or more carbon-carbon doublebonds. Preferred cycloalkenyl radicals are “lower cycloalkenyl” radicalshaving three to seven carbon atoms. Examples include radicals such ascyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term“halocycloalkyl” embraces radicals wherein any one or more of thecycloalkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohalocycloalkyl, dihalocycloalkyl andpolyhalocycloalkyl radicals. A monohalocycloalkyl radical, for oneexample, may have either a bromo, chloro or a fluoro atom within theradical. Dihalo radicals may have two or more of the same halo atoms ora combination of different halo radicals and polyhalocycloalkyl radicalsmay have more than two of the same halo atoms or a combination ofdifferent halo radicals. More preferred halocycloalkyl radicals are“lower halocycloalkyl” radicals having three to about eight carbonatoms. Examples of such halocycloalkyl radicals includefluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl,tetrafluorocyclohexyl, and dichlorocyclopropyl. The term“halocycloalkenyl” embraces radicals wherein any one or more of thecycloalkenyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl andpolyhalocycloalkenyl radicals.

The term “cycloalkoxy” embraces cycloalkyl radicals attached to an oxyradical. Examples of such radicals includes cyclohexoxy andcyclopentoxy. The term “cycloalkoxyalkyl” also embraces alkyl radicalshaving one or more cycloalkoxy radicals attached to the alkyl radical,that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals.Examples of such radicals include cyclohexoxyethyl. The “cycloalkoxy”radicals may be further substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide “halocycloalkoxy” and“halocycloalkoxyalkyl” radicals.

The term “cycloalkylalkoxy” embraces cycloalkyl radicals attached to analkoxy radical. Examples of such radicals includes cyclohexylmethoxy andcyclopentylmethoxy.

The term “cycloalkenyloxy” embraces cycloalkenyl radicals attached to anoxy radical. Examples of such radicals includes cyclohexenyloxy andcyclopentenyloxy. The term “cycloalkenyloxyalkyl” also embraces alkylradicals having one or more cycloalkenyloxy radicals attached to thealkyl radical, that is, to form monocycloalkenyloxyalkyl anddicycloalkenyloxyalkyl radicals. Examples of such radicals includecyclohexenyloxyethyl. The “cycloalkenyloxy” radicals may be furthersubstituted with one or more halo atoms, such as fluoro, chloro orbromo, to provide “halocycloalkenyloxy” and “halocycloalkenyloxyalkyl”radicals.

The term “cycloalkylenedioxy” radicals denotes cycloalkylene radicalshaving at least two oxygens bonded to a single cycloalkylene group.Examples of “alkylenedioxy” radicals include 1,2-dioxycyclohexylene.

The term “cycloalkylsulfinyl”, embraces cycloalkyl radicals attached toa sulfinyl radical, where cycloalkyl is defined as above.“Cycloalkylsulfinylalkyl”, embraces cycloalkylsulfinyl radicals attachedto an alkyl radical, where alkyl is defined as above. The term“Cycloalkylsulfonyl”, embraces cycloalkyl radicals attached to asulfonyl radical, where cycloalkyl is defined as above.“Cycloalkylsulfonylalkyl”, embraces cycloalkylsulfonyl radicals attachedto an alkyl radical, where alkyl is defined as above.

The term “cycloalkylalkanoyl” embraces radicals wherein one or more ofthe cycloalkyl carbon atoms are substituted with one or more carbonylradicals as defined below. Specifically embraced aremonocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples ofmonocarbonylcycloalkyl radicals include cyclohexylcarbonyl,cyclohexylacetyl, and cyclopentylcarbonyl. Examples ofdicarbonylcycloalkyl radicals include 1,2-dicarbonylcyclohexane.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. More preferred alkylthio radicals are “lower alkylthio” radicalshaving one to six carbon atoms. An example of “lower alkylthio” ismethylthio (CH₃—S—). The “alkylthio” radicals may be further substitutedwith one or more halo atoms, such as fluoro, chloro or bromo, to provide“haloalkylthio” radicals. Examples of such radicals includefluoromethylthio, chloromethylthio, trifluoromethylthio,difluoromethylthio, trifluoroethylthio, fluoroethylthio,tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.

The term “alkyl aryl amino” embraces radicals containing a linear orbranched alkyl radical, of one to ten carbon atoms, and one aryl radicalboth attached to an amino radical. Examples includeN-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, andN-methyl-4-trifluoromethoxyaniline.

The terms alkylamino denotes “monoalkylamino” and “dialkylamino”containing one or two alkyl radicals, respectively, attached to an aminoradical.

The terms arylamino denotes “monoarylamino” and “diarylamino” containingone or two aryl radicals, respectively, attached to an amino radical.Examples of such radicals include N-phenylamino and N-naphthylamino.

The term “aralkylamino”, embraces aralkyl radicals attached to an aminoradical, where aralkyl is defined as above. The term aralkylaminodenotes “monoaralkylamino” and “diaralkylamino” containing one or twoaralkyl radicals, respectively, attached to an amino radical. The termaralkylamino further denotes “monoaralkyl monoalkylamino” containing onearalkyl radical and one alkyl radical attached to an amino radical.

The term “arylsulfinyl” embraces radicals containing an aryl radical, asdefined above, attached to a divalent S(═O) atom. The term“arylsulfinylalkyl” denotes arylsulfinyl radicals attached to a linearor branched alkyl radical, of one to ten carbon atoms.

The term “arylsulfonyl”, embraces aryl radicals attached to a sulfonylradical, where aryl is defined as above. “arylsulfonylalkyl”, embracesarylsulfonyl radicals attached to an alkyl radical, where alkyl isdefined as above. The term “heteroarylsulfinyl” embraces radicalscontaining an heteroaryl radical, as defined above, attached to adivalent S(═O) atom. The term “heteroarylsulfinylalkyl” denotesheteroarylsulfinyl radicals attached to a linear or branched alkylradical, of one to ten carbon atoms. The term “Heteroarylsulfonyl”,embraces heteroaryl radicals attached to a sulfonyl radical, whereheteroaryl is defined as above. “Heteroarylsulfonylalkyl”, embracesheteroarylsulfonyl radicals attached to an alkyl radical, where alkyl isdefined as above.

The term “aryloxy” embraces aryl radicals, as defined above, attached toan oxygen atom. Examples of such radicals include phenoxy,4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,3-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy,3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy,3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy,3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy,4-tert-butylphenoxy, 3-pentafluoroethylphenoxy, and3-(1,1,2,2-tetrafluoroethoxy)phenoxy.

The term “aroyl” embraces aryl radicals, as defined above, attached toan carbonyl radical as defined above. Examples of such radicals includebenzoyl and toluoyl.

The term “aralkanoyl” embraces aralkyl radicals, as defined herein,attached to an carbonyl radical as defined above. Examples of suchradicals include, for example, phenylacetyl.

The term “aralkoxy” embraces oxy-containing aralkyl radicals attachedthrough an oxygen atom to other radicals. More preferred aralkoxyradicals are “lower aralkoxy” radicals having phenyl radicals attachedto lower alkoxy radical as described above. Examples of such radicalsinclude benzyloxy, 1-phenylethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethylbenzyloxy, 3,5-difluorobenyloxy, 3-bromobenzyloxy,4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, and2-phenylethoxy.

The term “aryloxyalkyl” embraces aryloxy radicals, as defined above,attached to an alkyl group. Examples of such radicals includephenoxymethyl.

The term “haloaryloxyalkyl” embraces aryloxyalkyl radicals, as definedabove, wherein one to five halo radicals are attached to an aryloxygroup.

The term “heteroaroyl” embraces heteroaryl radicals, as defined above,attached to an carbonyl radical as defined above. Examples of suchradicals include furoyl and nicotinyl.

The term “heteroaralkanoyl” embraces heteroaralkyl radicals, as definedherein, attached to an carbonyl radical as defined above. Examples ofsuch radicals include, for example, pyridylacetyl and furylbutyryl.

The term “heteroaralkoxy” embraces oxy-containing heteroaralkyl radicalsattached through an oxygen atom to other radicals. More preferredheteroaralkoxy radicals are “lower heteroaralkoxy” radicals havingheteroaryl radicals attached to lower alkoxy radical as described above.

The term “haloheteroaryloxyalkyl” embraces heteroaryloxyalkyl radicals,as defined above, wherein one to four halo radicals are attached to anheteroaryloxy group.

The term “heteroarylamino” embraces heterocyclyl radicals, as definedabove, attached to an amino group. Examples of such radicals includepyridylamino.

The term “heteroarylaminoalkyl” embraces heteroarylamino radicals, asdefined above, attached to an alkyl group. Examples of such radicalsinclude pyridylmethylamino.

The term “heteroaryloxy” embraces heterocyclyl radicals, as definedabove, attached to an oxy group. Examples of such radicals include2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and4-pyridyloxy.

The term “heteroaryloxyalkyl” embraces heteroaryloxy radicals, asdefined above, attached to an alkyl group. Examples of such radicalsinclude 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.

The term “arylthio” embraces aryl radicals, as defined above, attachedto an sulfur atom. Examples of such radicals include phenylthio.

The term “arylthioalkyl” embraces arylthio radicals, as defined above,attached to an alkyl group. Examples of such radicals includephenylthiomethyl.

The term “alkylthioalkyl” embraces alkylthio radicals, as defined above,attached to an alkyl group. Examples of such radicals includemethylthiomethyl. The term “alkoxyalkyl” embraces alkoxy radicals, asdefined above, attached to an alkyl group. Examples of such radicalsinclude methoxymethyl.

The term “carbonyl” denotes a carbon radical having two of the fourcovalent bonds shared with an oxygen atom. The term “carboxy” embraces ahydroxyl radical, as defined above, attached to one of two unsharedbonds in a carbonyl group. The term “carboxamide” embraces amino,monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino,and dicycloalkylamino radicals, attached to one of two unshared bonds ina carbonyl group. The term “carboxamidoalkyl” embraces carboxamideradicals, as defined above, attached to an alkyl group. The term“carboxyalkyl” embraces a carboxy radical, as defined above, attached toan alkyl group. The term “carboalkoxy” embraces alkoxy radicals, asdefined above, attached to one of two unshared bonds in a carbonylgroup. The term “carboaralkoxy” embraces aralkoxy radicals, as definedabove, attached to one of two unshared bonds in a carbonyl group. Theterm “monocarboalkoxyalkyl” embraces one carboalkoxy radical, as definedabove, attached to an alkyl group. The term “dicarboalkoxyalkyl”embraces two carboalkoxy radicals, as defined above, attached to analkylene group. The term “monocyanoalkyl” embraces one cyano radical, asdefined above, attached to an alkyl group. The term “dicyanoalkylene”embraces two cyano radicals, as defined above, attached to an alkylgroup. The term “carboalkoxycyanoalkyl” embraces one cyano radical, asdefined above, attached to an carboalkoxyalkyl group.

The term “acyl”, alone or in combination, means a carbonyl orthionocarbonyl group bonded to a radical selected from, for example,hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl,haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy,arylthio, and alkylthioalkyl. Examples of “acyl” are formyl, acetyl,benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.The term “haloalkanoyl” embraces one or more halo radicals, as definedherein, attached to an alkanoyl radical as defined above. Examples ofsuch radicals include, for example, chloroacetyl, trifluoroacetyl,bromopropanoyl, and heptafluorobutanoyl. The term “diacyl”, alone or incombination, means having two or more carbonyl or thionocarbonyl groupsbonded to a radical selected from, for example, alkylene, alkenylene,alkynylene, haloalkylene, alkoxyalkylene, aryl, heterocyclyl,heteroaryl, aralkyl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl.Examples of “diacyl” are phthaloyl, malonyl, succinyl, adipoyl, and thelike.

The term “benzylidenyl” radical denotes substituted and unsubstitutedbenzyl groups having attachment points for two covalent bonds. Oneattachment point is through the methylene of the benzyl group with theother attachment point through an ortho carbon of the phenyl ring. Themethylene group is designated for attached to the lowest numberedposition. Examples include the base compound benzylidene of structure:

The term “phenoxylidenyl” radical denotes substituted and unsubstitutedphenoxy groups having attachment points for two covalent bonds. Oneattachment point is through the oxy of the phenoxy group with the otherattachment point through an ortho carbon of the phenyl ring. The oxygroup is designated for attached to the lowest numbered position.Examples include the base compound phenoxylidene of structure:

The term “phosphono” embraces a pentavalent phosphorus attached with twocovalent bonds to an oxygen radical. The term “dialkoxyphosphono”denotes two alkoxy radicals, as defined above, attached to a phosphonoradical with two covalent bonds. The term “diaralkoxyphosphono” denotestwo aralkoxy radicals, as defined above, attached to a phosphono radicalwith two covalent bonds. The term “dialkoxyphosphonoalkyl” denotesdialkoxyphosphono radicals, as defined above, attached to an alkylradical. The term “diaralkoxyphosphonoalkyl” denotes diaralkoxyphosphonoradicals, as defined above, attached to an alkyl radical.

Said “alkyl”, “alkenyl”, “alkynyl”, “alkanoyl”, “alkylene”,“alkenylene”, “benzylidenyl”, “phenoxylidenyl”, “hydroxyalkyl”,“haloalkyl”, “haloalkylene”, “haloalkenyl”, “alkoxy”, “alkenyloxy”,“alkenyloxyalkyl”, “alkoxyalkyl”, “aryl”, “perhaloaryl”, “haloalkoxy”,“haloalkoxyalkyl”, “haloalkenyloxy”, “haloalkenyloxyalkyl”,“alkylenedioxy”, “haloalkylenedioxy”, “heterocyclyl”, “heteroaryl”,“hydroxyhaloalkyl”, “alkylsulfonyl”, “haloalkylsulfonyl”,“alkylsulfonylalkyl”, “haloalkylsulfonylalkyl”, “alkylsulfinyl”,“alkylsulfinylalkyl”, “haloalkylsulfinylalkyl”, “aralkyl”,“heteroaralkyl”, “perhaloaralkyl”, “aralkylsulfonyl”,“aralkylsulfonylalkyl”, “aralkylsulfinyl”, “aralkylsulfinylalkyl”,“cycloalkyl”, “cycloalkylalkanoyl”, “cycloalkylalkyl”, “cycloalkenyl”,“halocycloalkyl”, “halocycloalkenyl”, “cycloalkylsulfinyl”,“cycloalkylsulfinylalkyl”, “cycloalkylsulfonyl”,“cycloalkylsulfonylalkyl”, “cycloalkoxy”, “cycloalkoxyalkyl”,“cycloalkylalkoxy”, “cycloalkenyloxy”, “cycloalkenyloxyalkyl ”,“cycloalkylenedioxy”, “halocycloalkoxy”, “halocycloalkoxyalkyl”,“halocycloalkenyloxy”, “halocycloalkenyloxyalkyl”, “alkylthio”,“haloalkylthio”, “alkylsulfinyl”, “amino”, “oxy”, “thio”, “alkylamino”,“arylamino”, “aralkylamino”, “arylsulfinyl”, “arylsulfinylalkyl”,“arylsulfonyl”, “arylsulfonylalkyl”, “heteroarylsulfinyl”,“heteroarylsulfinylalkyl”, “heteroarylsulfonyl”,“heteroarylsulfonylalkyl”, “heteroarylamino”, “heteroarylaminoalkyl”,“heteroaryloxy”, “heteroaryloxylalkyl”, “aryloxy”, “aroyl”,“aralkanoyl”, “aralkoxy”, “aryloxyalkyl”, “haloaryloxyalkyl”,“heteroaroyl”, “heteroaralkanoyl”, “heteroaralkoxy”,“heteroaralkoxyalkyl”, “arylthio”, “arylthioalkyl”, “alkoxyalkyl”,“acyl” and “diacyl” groups defined above may optionally have 1 to 5non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamnino, heteroarylaminoalkyl,heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy,alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy,cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl,aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partiallysaturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl,arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido,carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl,diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

The term “spacer” can include a covalent bond and a linear moiety havinga backbone of 1 to 7 continous atoms. The spacer may have 1 to 7 atomsof a univalent or multi-valent chain. Univalent chains may beconstituted by a radical selected from ═C(H)—, ═C(R₁₇)—, —O—, —S—,—S(O)—, —S(O)₂—, —NH—, —N(R₁₇)—, —N═, —CH(OH)—, ═C(OH)—, —CH(OR₁₇)—,═C(OR₁₇)—, and —C(O)— wherein R₁₇ is selected from alkyl, alkenyl,alkynyl, aryl, heteroaryl, ralkyl, aryloxyalkyl, alkoxyalkyl,alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl.Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4 or 5 or 6atoms with a side chain. The chain may be constituted of one or moreradicals selected from: lower alkylene, lower alkenyl, —O—, —O—CH₂—,—S—CH₂—, —CH₂CH₂—, ethenyl, —CH═CH(OH)—, —OCH₂O—, —O(CH₂)₂O—, —NHCH₂—,—OCH(R₁₇)O—, —O(CH₂CHR₁₇)O—, —OCF₂O—, —O(CF₂)₂O—, —S—, —S(O)—, —S(O)₂—,—N(H)—, —N(H)O—, —N(R₁₇)O—, —N(R₁₇)—, —C(O)—, —C(O)NH—, —C(O)NR₁₇—, —N═,—OCH₂—, —SCH₂—, S(O)CH₂—, —CH₂C(O)—, —CH(OH)—, ═C(OH)—, —CH(OR₁₇)—,═C(OR₁₇)—, S(O)₂CH₂—, and —NR₁₇CH₂— and many other radicals definedabove or generally known or ascertained by one of skill-in-the art. Sidechains may include substituents such as 1 to 5 non-hydrido substituentssuch as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkyl sulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy,heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy,alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl,aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partiallysaturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl,arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl,cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono,and diaralkoxyphosphonoalkyl.

Compounds of the present invention can exist in tautomeric, geometric orstereoisomeric forms. The present invention contemplates all suchcompounds, including cis- and trans-geometric isomers, E- andZ-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers,l-isomers, the racemic mixtures thereof and other mixtures thereof, asfalling within the scope of the invention. Pharmaceutically acceptablesales of such tautomeric, geometric or stereoisomeric forms are alsoincluded within the invention.

The terms “cis” and “trans” denote a form of geometric isomerism inwhich two carbon atoms connected by a double bond will each have ahydrogen atom on the same side of the double bond (“cis”) or on oppositesides of the double bond (“trans”).

Some of the compounds described contain alkenyl groups, and are meant toinclude both cis and trans or “E” and “Z” geometric forms.

Some of the compounds described contain one or more stereocenters andare meant to include R, S, and mixtures of R and S forms for eachstereocenter present.

Some of the compounds described herein may contain one or more ketonicor aldehydic carbonyl groups or combinations thereof alone or as part ofa heterocyclic ring system. Such carbonyl groups may exist in part orprincipally in the “keto” form and in part or principally as one or more“enol” forms of each aldehyde and ketone group present. Compounds of thepresent invention having aldehydic or ketonic carbonyl groups are meantto include both “keto” and “enol” tautomeric forms.

Some of the compounds described herein may contain one or more amidecarbonyl groups or combinations thereof alone or as part of aheterocyclic ring system. Such carbonyl groups may exist in part orprincipally in the “keto” form and in part or principally as one or more“enol” forms of each amide group present. Compounds of the presentinvention having amidic carbonyl groups are meant to include both “keto”and “enol” tautomeric forms. Said amide carbonyl groups may be both oxo(C═O) and thiono (C═S) in type.

Some of the compounds described herein may contain one or more imine orenamine groups or combinations thereof. Such groups may exist in part orprincipally in the “imine” form and in part or principally as one ormore “enamine” forms of each group present. Compounds of the presentinvention having said imine or enamine groups are meant to include both“imine” and “enamine” tautomeric forms.

The following general synthetic sequences are useful in making thepresent invention. Abbreviations used in the schemes are as follows:“AA” represents amino acids, “BINAP” represents2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, “Boc” representstert-butyloxycarbonyl, “BOP” representsbenzotriazol-1-yl-oxy-tris-(dimethylamino), “bu” represents butyl, “dba”represents dibenzylideneacetone, “DCC” represents1,3-dicyclohexylcarbodiimide, “DIBAH” represents diisobutylaluminumhydride, “DIPEA” represents diisopropylethylamine, “DMF” representsdimethylformamide, “DMSO” represents dimethylsulfoxide, “Fmoc”represents 9-fluorenylmethoxycarbonyl, “LDA” represents lithiumdiisopropylamide, “PHTH” represents a phthaloyl group, “pnZ” represents4-nitrobenzyloxycarbonyl, “PTC” represents a phase transfer catalyst,“p-TsOH” represents paratoluenesulfonic acid, “TBAF” representstetrabutylammonium fluoride, “TBTU” represents2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate,“TEA” represents triethylamine, “TFA” represents trifluoroacetic acid,“THF” represents tetrahydrofuran, “TMS” represents trimethylsilyl, and“Z” represents benzyloxycarbonyl.

PHARMACEUTICAL UTILITY AND COMPOSITION

The present invention comprises a pharmaceutical composition comprisinga therapeutically-effective amount of a compound of Formulas V-H, V,VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, in association with atleast one pharmaceutically-acceptable carrier, adjuvant or diluent.

The present invention also comprises a treatment and prophylaxis ofcoronary artery disease and other CETP-mediated disorders in a subject,comprising administering to the subject having such disorder atherapeutically-effective amount of a compound of Formula V-H:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄,R₁₅, R₁₆, R₁₉, X, Y, and Z are as defined above for the compounds ofFormula V-H;

or a pharmaceutically-acceptable salt thereof.

As a further embodiment, compounds of the present invention of FormulasV-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, or apharmaceutically-acceptable salt thereof as defined above and furtherincluding those, wherein R₁₆ is a covalent single bond linked to a pointof bonding of R₄ or R₈ when R₂ is alkyl, R₂ and R₁₄ are taken togetherto form a —N═ spacer group, and R₂ and R₁₅ are taken together to form a—N═ spacer group, comprise a treatment and prophylaxis of coronaryartery disease and other CETP-mediated disorders in a subject,comprising administering to the subject having such disorder atherapeutically-effective amount of compounds of Formulas V-H, V, VII-H,VII, VII-2, VII-3, VII-4, and Cyclo-VII, of the present invention or apharmaceutically-acceptable salt thereof.

Compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, andCyclo-VII including those, wherein R₁₆ is a covalent single bond linkedto a point of bonding of R₄ or R₈ when R₂ is alkyl, R₂ and R₁₄ are takentogether to form a —N═ spacer group, and R₂ and R₁₅ are taken togetherto form a —N═ spacer group, are capable of inhibiting activity ofcholesteryl ester transfer protein (CETP), and thus could be used in themanufacture of a medicament, a method for the prophylactic ortherapeutic treatment of diseases mediated by CETP, such as peripheralvascular disease, hyperlipidaemia, hypercholesterolemia, and otherdiseases attributable to either high LDL and low HDL or a combination ofboth, or a procedure to study the mechanism of action of the cholesterylester transfer protein (CETP) to enable the design of better inhibitors.The compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, andCyclo-VII would be also useful in prevention of cerebral vascularaccident (CVA) or stroke.

Also included in the family of compounds of Formulas V-H, V, VII-H, VII,VII-2, VII-3, VII-4, and Cyclo-VII are the pharmaceutically-acceptablesalts thereof. The term “pharmaceutically-acceptable salts” embracessalts commonly used to form alkali metal salts and to form additionsalts of free acids or free bases. The nature of the salt is notcritical, provided that it is pharmaceutically acceptable. Suitablepharmaceutically-acceptable acid addition salts of compounds of FormulaV-H may be prepared from inorganic acid or from an organic acid.Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, examples of which are formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucoronic, maleic, fumaric, pyruvic, aspartic, glutamnic, benzoic,anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic,benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic,galacturonic acid. Suitable pharmaceutically-acceptable base additionsalts of compounds of Formula V-H include metallic salts made fromaluminum, calcium, lithium, magnesium, potassium, sodium and zinc ororganic salts made from N,N′-dibenzylethyleneldiamine, choline,chloroprocaine, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procain. All of these salts may be prepared byconventional means from the corresponding compounds of Formulas V-H, V,VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII by reacting, for example,the appropriate acid or base with the compounds of Formulas V-H, V,VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formula V-H inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The active compounds andcomposition may, for example, be administered orally, intravascularly,intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compounds which are administeredand the dosage regimen for treating a disease condition with thecompounds and/or compositions of this invention depends on a variety offactors, including the age, weight, sex and medical condition of thesubject, the severity of the disease, the route and frequency ofadministration, and the particular compound employed, and thus may varywidely.

The pharmaceutical compositions may contain active ingredients in therange of about 0.1 to 2000 mg, and preferably in the range of about 0.5to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, andpreferably between about 0.5 and about 20 mg/kg body weight, may beappropriate. The daily dose can be administered in one to four doses perday.

The compounds may be formulated in topical ointment or cream, or as asuppository, containing the active ingredients in a total amount of, forexample, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably0.4 to 15% w/w. When formulated in an ointment, the active ingredientsmay be employed with either paraffinic or a water-miscible ointmentbase.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

For therapeutic purposes, the active compounds of this combinationinvention are ordinarily combined with one or more adjuvants appropriateto the indicated route of administration. If administered per os, thecompounds may be admixed with lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

All mentioned references are incorporated by reference as if herewritten.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

GENERAL SYNTHETIC PROCEDURES

The compounds of the present invention can be synthesized, for example,according to the following procedures of Schemes 1 through 59 below,wherein the substituents are as defined for Formulas V-H, V, VII-H, VII,VII-2, VII-3, VII-4, and Cyclo-VII above except where further noted.

Synthetic Schemes 1 and 2 shows the preparation of compounds of formulaXIII (“Generic Secondary Amines”) which are intermediates in thepreparation of the compounds of the present invention corresponding toFormula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryltertiary omegahydroxyalkylamines”), Formula V (“Generic SubstitutedPolycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII(“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”),and Formula VII-H (“Generic Substituted Polycyclic Heteroaryltertiary-2-hydroxyalkylamines”) wherein A and Q are independently aryland heteroaryl. Schemes 1 and 2, taken together, prepare tertiaryoxyalkylamine compounds of the present invention by addition of ahalogenated, oxygen containing precursor to a secondary amine tointroduce an oxy containing alkyl group wherein the two groups making upthe secondary amine both are made up of aromatic groups or both groupscontain aromatic rings wherein said aromatic rings maybe 0 to 2 arylrings and 0 to 2 heteroaryl rings.

The “Generic Imine” corresponding to Formula XII can be prepared throughdehydration techniques generally known in the art and the preferredtechnique depending on the nature of “Generic Amine-1” of Formula X byreacting it with the “Generic Carbonyl Compound” of Formula XI. Forexample, when Z is a covalent bond, methylene, methine substituted withanother subsitutent, ethylene, or another subsituent as defined inFormula V-H, the two reactants (X and XI) react by refluxing them in anaprotic solvent, such as hexane, toluene, cyclohexane, benzene, and thelike, using a Dean-Stark type trap to remove water. After about 2-8hours or until the removal of water is complete, the aprotic solvent isremoved in vacuo to yield the “Generic Imine” of Formula XII.Alternately, when Z is an oxygen, the “Generic Imine” is an oximederivative. Oxime type “Generic Imine” compounds are readily preparedfrom the corresponding O-substituted hydroxylamine and the appropriatealdehyde or ketone type “Generic Carbonyl Compound”. Suitable proceduresare described by Shriner, Fuson, and Curtin in The SystematicIndentification of Organic Compounds, 5th Edition, John Wiley & Sons andby Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, JohnWiley & Sons, which are incorporated herein by reference. Alternately,when Z is a nitrogen, the “Generic Imine” is a hydrazone derivative.Hydrazone type “Generic Imine” compounds are readily prepared from thecorresponding hydrazine and the appropriate aldehyde or ketone type“Generic Carbonyl Compound”. Suitable procedures for forming thehydrazone imines are also described by Shriner, Fuson, and Curtin in TheSystematic Indentification of Organic Compounds, 5th Edition, John Wiley& Sons, and by Fieser and Fieser in Reagents for Organic Synthesis,Volume 1, John Wiley & Sons, which are incorporated herein by reference.

Scheme 1 shows the preparation of “Generic Imine” compounds in which theamine functionality is bonded to Z;Z is bonded to A; and Y is bonded toQ. One of skill in the art will recognize that A and Q as defined can bestructurally interchanged to prepare “Generic Imine” compounds withsimilar, identical or different structures.

The “Generic Secondary Amines” of Formula XIII can be prepared from thecorresponding “Generic Imine” of Formula XII in several ways.

For example, in one synthetic scheme (Reduction Method-1), which ispreferred when Z is a nitrogen, the “Generic Imine” hydrazone of FormulaXII is partially or completely dissolved in lower alkanols such asethanol or like solvent containing sufficient organic acid such asacetic acid or mineral acid such as HCl or sulfuric acid to neutralizethe hydrazone as described in WO Patent Application No. 9738973, SwissPatent CH 441366 and U.S. Pat. Nos. 3,359,316 and 3,334,017, which areincorporated herein by reference. The resulting mixture is thenhydrogenated at 0-100° C., more preferrably 20-50° C., and mostpreferrably between 20-30° C. and pressures of 10-200 psi hydrogen ormore preferrably between 50-70 psi hydrogen in the presence of a noblemetal catalyst such as PtO₂. The mixture is cooled, and a base such assodium carbonate or sodium hydroxide added until the solution is neutralto just alkaline (pH 6-8).

Isolation of the desired product can be accomplished, for example, byremoving the ethanol, adding water, and extracting the aqueous-organicmixture twice with a solvent, such as diethyl ether or methylenechloride, that is immiscible with water. The combined solvent extract iswashed with saturated brine, dried with a drying agent such as anhydrousmagnesium sulfate, and concentrated in vacuo to yield the “GenericSecondary Amines” hydrazine of Formula XIII. If needed the “GenericSecondary Amines” hydrazine can be further purified by crystallization,distillation at reduced pressure, or liquid chromatography.

In another synthetic scheme (Reduction Method-2), which is preferredwhen Z is a single bond or carbon, the “Generic Imine” of Formula XII isslurried in a lower alcohol such as ethanol, methanol or like solvent at0-10° C. and solid sodium borohydride is added in batches over 5-10minutes at 0-10° C. with stirring. The reaction mixture is stirred below10° C. for 30-90 minutes and then is warmed gradually to 15-30° C. Afterabout 1-10 hours, the mixture is cooled and acid is added until theaqueous layer was just acidic (pH 5-7).

Isolation of the desired product can be accomplished, for example, byextracting the aqueous layer twice with a solvent, such as diethyl etheror methylene chloride, that is immiscible with water. The combinedsolvent extract is washed with saturated brine, dried with a dryingagent such as anhydrous MgSO4, and concentrated in vacuo to yield the“Generic Secondary Amines” amine, aniline, or amine of Formula XIII. Ifneeded the “Generic Secondary Amines” amine, aniline, or aminederivative can be further purified by crystallization, distillation atreduced pressure, or liquid chromatography.

In yet another synthetic scheme (Reduction Method-3), which is preferredwhen Z is an oxygen, the “Generic Imine” oxime of Formula XII isslurried in a lower alcohol solvent such methanol or like solvent at0-10° C. and acidified to a pH less than 4. Solid sodiumcyanoborohydride is added in batches over 30-90 minutes at 0-20° C. withstirring and addition of a suitable organic or mineral acid to keep thepH at or below 4. The reaction mixture is stirred and warmed graduallyto about 20-25° C. After about 1-10 hours, the mixture is cooled andbase added until the mixture was just slightly alkaline.

Isolation of the desired product can be accomplished, for example, byremoving the methanol or other low boiling solvent in vacuo. The residueis slurried with water and aqueous-organic mixture is extracted twicewith a solvent, such as diethyl ether or methylene chloride, that isimmiscible with water. The combined solvent extract is washed withsaturated brine, dried with a drying agent such as anhydrous MgSO₄, andconcentrated in vacuo to yield the “Generic Secondary Amines”hydroxylamine of Formula XIII. If needed the “Generic Secondary Amines”hydroxylamine can be further purified by crystallization, distillationat reduced pressure, or liquid chromatography.

The “Generic Secondary Amines” of Formula XIII can also be prepared,according to Scheme 1 by two alkylation procedures based on thenucleophilic substitution of bromides by amines. In one procedure,“Generic Amine-1” of Formula X is reacted with “Generic Bromide-1” ofFormula XXI. In another alkylation procedure, “Generic Amine-2” ofFormula XXII is reacted together with “Generic Bromide-2” of FormulaXXIII.

In one synthetic alkylation scheme (Alkylation Method-1), a “GenericAmine-1” of Formula X is reacted with a “Generic Bromide-2” of FormulaXXIII as described in Vogel's Textbook of Practical Organic Chemistry,Fifth Edition, 1989, pages 902 to 905 and references cited therein allof which are incorporated herein by reference. In this procedure, the“Generic Amine-1” is placed in a reaction vessel equipped with a refluxcondenser with the capability to either cool or heat the vessel asdictated by the reaction. A suitable “Generic Amine-1” will be selectedfrom primary amine and primary aromatic amine classes of compounds.Cooling may be needed and used should the reaction prove stronglyexothermic. Heating may be needed and used to drive the reaction tocompletion. A suitable solvent may also be used to dissolve the “GenericAmine-1”. Suitable solvents are hydrocarbons such as toluene, hexane,xylene, and cyclohexane, ethers, amides such as dimethylformamide,esters such as ethyl acetate, ketones such as acetone, and nitriles suchas acetonitrile or mixtures of two or more of these solvents. A suitablebase is also added to the reaction vessel. Suitable bases include cesiumcarbonate, calcium carbonate, sodium carbonate and sodium bicarbonate.The base will normally be added in at least a stoichmetric quantitycompared to the “Generic Amine-1” so as to neutralize liberated acid asit forms.

The “Generic Bromide-1” of Formula XXI is then added to the reactionvessel in portions so as to minimize the rate of heat evolution andminimize the concentration of the “Generic Bromide-1”. The “GenericBromide-1” will be selected from primary and secondary organic alkyl andsubstituted alkyl halide compounds. The halide will preferrably be abromide although iodides and chlorides may also be generally used. Oneof skill in the art will also be able to readily select and utilizeorganic alkyl and substituted alkyl compounds containing readilydisplaceable primary and secondary groups such as tosylates, mesylates,triflates, and the like. Alternately, the halides can be generallyprepared from the corresponding alcohols by reaction with, for example,concentrated hydrohalic acids such as HBr or by reaction with phosphorustrihalides such as PBr₃ as described in Fieser and Fieser in Reagentsfor Organic Synthesis, Volume 1, John Wiley & Sons, which areincorporated herein by reference. The appropriate alcohols can beconverted to tosylates, mesylates, and triflates using proceduresdescribed below.

Addition of the “Generic Bromide-1” is carried out over a period of afew minutes to several hours at temperatures between 0 and 150° C.Preferrably, the addition will take 30-120 minutes at a temperature of 0to 50° C. The reaction can be stirred until completion. Completion canbe monitored, for example, spectroscopically using nuclear magneticresonance or chromatographically using thin layer, liquid, or gaschromatographic procedures. If the reaction does not proceed tocompletion, the reactants may be heated until completion is obtained andverified.

Isolation of the desired product can be accomplished, for example, whena water immiscible solvent was used for the reaction, by adding water tothe finished reaction. Additional base such as sodium carbonate can beadded to ensure the reaction is basic (pH of 9 to 11). The organic layercontaining the “Generic Secondary Amine” is washed with saturated brine,dried with a drying agent such as anhydrous MgSO₄, and concentrated invacuo to yield the “Generic Secondary Amine” amine, aniline, or amine ofFormula XIII. If needed the “Generic Secondary Amine” amine, aniline, oramine derivative can be further purified by crystallization,distillation at reduced pressure, or liquid chromatography.

In a second synthetic alkylation scheme (Alkylation Method-2), a“Generic Amine-2” of Formula XXII is reacted with a “Generic Bromide-2”of Formula XXIII in a method employing palladium catalyzedcarbon-nitrogen bond formation. Suitable procedures for this conversionare described in Wagaw and Buchwald, J. Org. Chem.(1996), 61, 7240-7241,Wolfe, Wagaw and Buchwald, J. Am. Chem. Soc. (1996), 118, 7215-7216, andWolfe and Buchwald, Tetrahedron Letters (1997), 38(36), 6359-6362 andreferences cited therein all of which are incorporated herein byreference. The preferred “Generic Bromide-2” of Formula XXIII aregenerally aryl bromides, aryl triflates, and heteroaryl bromides.

The “Generic Amine-1” and “Generic Amine-2” amines, hydroxylamines, andhydrazines, the “Generic Carbonyl Compound” aldehydes, ketones,hydrazones, and oximes, and “Generic Bromide-1” and “Generic Bromide-2”halides, tosylates, mesylates, triflates, and precursor alcoholsrequired to prepare the “Generic Secondary Amine” compounds areavailable from commercial sources, can be prepared by one skilled in theart from published procedures, and/or can be obtained using specificprocedures shown in Schemes 42, 43, and 44. Commercial sources includebut are not limited to Aldrich Chemical, TCI-America,Lancaster-Synthesis, Oakwood Products, Acros Organics, and MaybridgeChemical. Disclosed procedures for “Generic Amine” amines,hydroxylamines, and hydrazines include Sheradsky and Nov, J. Chem. Soc.,Perkin Trans.1 (1980), (12), 2781-6; Marcoux, Doye, and Buchwald, J. Am.Chem. Soc. (1997), 119, 1053-9; Sternbach and Jamison, Tetrahedron Lett.(1981), 22(35), 3331-4; U.S. Pat. No. 5,306,718; EP No. 314435; WO No.9001874; WO No. 9002113; JP No. 05320117; WO No. 9738973; Swiss PatentNo. CH 441366; U.S. Pat. Nos. 3,359,316 and 3,334,017; and referencescited therein which are incorporated herein by reference. Representativespecific “Generic Secondary Amine” of Formula XIII compounds useful forthe preparation of compounds of the present invention are listed inTables 3, 4, and 5.

As summarized in the general Scheme 1 and specific descriptions above,Schemes 3, 4, 9, and 10 illustrate the principles of Scheme 1 for thepreparation of specifically substituted “Secondary Heteroaryl Amines”(XIIIA-H) having 0 to 2 aryl groups and 0 to 2 aromatic heterocyclylgroups and “Secondary Phenyl Amines” (XIII-A) having two aryl groups.

Synthetic Scheme 2 shows the preparation of the class of compounds ofthe present invention corresponding to Formula V-H (“Generic SubstitutedPolycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”),Formula V (“Generic Substituted Polycyclic Aryl tertiaryomegahydroxyalkylamines”), Formula VII (“Generic Substituted PolycyclicAryl tertiary-2-hydroxyalkylamines”), and Formula VII-H (“GenericSubstituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”)wherein A and Q are independently aryl and heteroaryl.

Derivatives of “Generic Substituted Polycyclic Aryl and Heteroaryltertiary omegahydroxyalkylamines” and “Generic Substituted PolycyclicAryl tertiary omegahydroxyalkylamines”, wherein A and Q areindependently aryl and heteroaryl, in which the hetero atom (—O—) isattached to an alkyl group removed from the amine by three or morecarbons are readily prepared by anion chemistry using Method B of Scheme2. The anion of “Generic Secondary Amine” amines, hydroxylamines, andhydrazines of Formula XIII are readily formed by dissolving the specificamine, hydroxylamine, or hydrazine in an aprotic solvent, such astetrahydrofuran, toluene, ether, dimethylformamide, anddimethylformamide, under anhydrous conditions. The solution is cooled toa temperature between −78 and 0° C., preferrably between −78 and −60° C.and the anion formed by the addition of at least one equivalent of astrong, aprotic, non-nucleophillic base such as NaH or n-butyllithiumunder an inert atmosphere for each acidic group present. Maintaining thetemperature between −78 and 0° C., preferrably between −78 and −60° C.,with suitable cooling, an appropriate alkyl

TABLE 3 Structure of “Secondary Phenyl Amine” Reagents. (XIIIA)

Reagent Number R₄ R₅ R₆ R₇ R₉ R₁₀ R₁₁ Y R₁₄  1N H phenoxy H H H OCF₂CF₂HH CH H  2N H OCF₃ H H H OCF₂CF₂H H CH H  3N F H H F H OCF₂CF₂H H CH H 4N H F H H H OCF₂CF₂H H CH H  5N H phenoxy H H H OCF₃ H CH H  6N H OCF₃H H H OCF₃ H CH H  7N H H phenyl H H OCF₃ H CH H  8N H phenyl H H H OCF₃H CH H  9N H H H H H OCF₃ H CH H 10N H Br H H H OCF₃ H CH H 11N H CF₃ FH H CF₃ H CH H 12N H CH₃ H H H CF₃ H CH H 13N H CF₃ H H H CF₃ H CH H 14NH CH₃ H H H OCF₃ H CH H 15N H F F H H OCF₃ H CH H 16N H Br H H H CF₃ HCH H 17N H CF₃ F H H OCF₃ H CH H 18N H F H H H OCF₃ H CH H 19N H Cl H HH OCF₃ H CH H 20N H F H H H CF₃ H CH H 21N H F F H H CF₃ H CH H 22N H ClH H H CF₃ H CH H 23N H F H H H phenoxy H CH H 24N H CF₃ Cl H H CH₃ H CHH 25N H CF₃ F H H CH₃ H CH H 26N H H H H H CF₃ H CH H 27N F F H H H CF₃H CH H 28N H H OCH₃ H H CF₃ H CH H 29N H F F H H CH₃ H CH H 30N H OCH₃ HH H CH₃ H CH H 31N H H CH₃ H H H H CH H 32N H Cl H H H H H CH H 33N H FH H H F H CH H 34N H H OCH₃ H H CH₃ H CH H 35N H H H H H H H CH H 36N HH CH₃ H H CH₃ H CH H 37N H H Cl H H H H CH H 38N H F H H H 3-CF₃-phenoxyH CH H 39N H F H H H 4-CH₃O-phenoxy H CH H 40N H F H H H 4-Cl-phenoxy HCH H 41N H F H H H H H CH H 42N H F H H H CH₃ H CH H 43N H F H F H CH₃ HCH H 44N F F H H H CH₃ H CH H 45N H Cl H H H CH₃ H CH H 46N H CH₃ H H HCH₃ H CH H 48N H H CH₃ H H CF₃ H CH H 51N H H CH₃ H H F H CH H 52N H CF₃H H H F H CH H 53N H CF₃ H H H CH₃ H CH H 54N H OCH₃ H H H CF₃ H CH H56N H H CH₃ H H CF₃ H CH H 57N H phenoxy H H H H OCF₃ CH H 58N H H H H HH OCF₃ CH H 59N H OCF₃ H H H H OCF₃ CH H 60N H CF₃ F H H H CF₃ CH H 61NH H OCH₃ H H H CF₃ CH H 62N H CH₃ H H H H CF₃ CH H 63N H Cl H H H H CF₃CH H 64N H CF₃ H H H H OCF₃ CH H 65N H F H H H H OCF₃ CH H 66N H F H F HH OCF₃ CH H 67N H Br H H H H OCF₃ CH H 68N H Cl H H H H OCF₃ CH H 69N HF F H H H OCF₃ CH H 70N H F H H H H phenyl CH H 71N H CH₃ H H H H OCF₃CH H 72N H F F H H H CF₃ CH H 73N H Cl H H H H CH₃ CH H 74N H OCH₃ H H HH CH₃ CH H 75N H F H H H H CH₃ CH H 76N F F H H H H OCF₃ CH H 78N H HOCH₃ H H H CH₃ CH H 79N H H CH₃ H H H CH₃ CH H 80N H CH₃ H H H H CH₃ CHH 82N H F F H H H CH₃ CH H 83N H F H F H H CH₃ CH H 84N F F H H H H CH₃CH H 85N F CF₃ H H H H CH₃ CH H 86N H H CH₃ H H H CF₃ CH H 88N H CF₃ H HH H CH₃ CH H 90N H H CF₃ H H H CH₃ CH H 92N H CF₃ F H H H CH₃ CH H

TABLE 4 Structure of “Secondary Phenyl Amine” Reagents (Z is covalentbond; there is no R₁₅ substituent; R₄ and R₁₃ equal H). (XIII-A)

Spacer Rgnt. Bond No. R₅ R₆ R₇ R₈ Y R₁₄ R₉ R₁₀ R₁₁ R₁₂ Spacer Points 93NBr H H CH H H H OCF₃ —O— R₈ + R₉ 94N OCF₃ H H CH H H H OCF₃ — R₈ + R₉95N Br H H C H OCF₃ H H ═CH— R₈ + R₁₄ 96N OH OH H H CH H H C₆H₅O H Hnone none 97N C₆H₅O H H H CH H H OH OH H none none 98N 3-pyridyl H H HCH H H CF₃ H H none none 99N SO₂N H H H CH H H OCF₃ H H none none (CH₃)₂100N SO₂CH₃ H H H CH H H OCF₃ H H none none 101N C₆H₅O H H H CH H HC₆H₅O H H none none 102N CF₃O H H H CH H H C₆H₅O H H none none 103N C₆H₅H H H CH H H C₆H₅O H H none none 104N H C₆H₅ H H CH H H C₆H₅O H H nonenone 105N C₆H₅O H H H CH H H 4-Cl—C₆H₄O H H none none 106N CF₃O H H H CHH H 4-Cl—C₆H₄O H H none none 107N C₆H₅O H H H CH H H 3,4-Cl—C₆H₃O H Hnone none 108N CF₃O H H H CH H H 3,4-Cl—C₆H₃O H H none none 109N CF₃O HH H CH H H 3,5-Cl—C₆H₃O H H none none 110N CF₃O H H H CH H H 3-CH₃O— H Hnone none C₆H₄O 111N CF₃O H H H CH H H H 3-CH₃O— H none none C₆H₄O 112NCF₃O H H H CH H H 3-CF₃—C₆H₄O H H none none 113N CF₃O H H H CH H HC₆H₅—CH₂O H H none none 114N CF₃O H H H CH H H C₆H₅—CH₂O CH₃O H nonenone 115N CF₃O H H H CH H H C₆H₅—CH₂O C₆H₅— H none none CH₂O 116N CF₃O HH H CH H H ethoxy H H none none 117N CF₃O H H H CH H H CH₃CO₂ H H nonenone 118N CF₃O H H H CH H H HOCH₂— H H none none CH₂O 119N CF₃O H H H CHH H

H H none none 120N CF₃O H H H CH H H R₁₀ + R₁₁ = OCH₂O H none none 121NCF₃O H H H CH H H R₁₀ + R₁₁ = OCH₂CH₂O H none none 122N CF₃O H H H CH HH CH₃O CH₃O H none none 123N CF₃O H H H CH H H ethoxy CH₃O H none none124N CF₃O H H H CH H H ethoxy ethoxy H none none 125N CF₃O H H H CH H HCH₃CO₂ CH₃CO₂ H none none 126N CF₃O H H H CH H H CH₃O CH₃CO₂ H none none127N CF₃O H H H CH H H n-butoxy H H none none 128N CF₃O H H H CH H HCH₃O H H none none 129N CF₃O H H H CH H H H CH₃O H none none 130N CH₃O HH H CH H H CH₃O H H none none 131N CH₃O H H H CH H H H CF₃O H none none132N CF₃O H H H CH H H H ethoxy H none none 133N CF₃O H H H CH H H Hn-propoxy H none none 134N C₆H₅—CH₂O H H H CH H H CF₃O H H none none135N C₆H₅—CH₂O H H H CH H H C₆H₅O H H none none 136N ethoxy H H H CH H HCF₃O H H none none 137N R₅ + R₆ = OCH₂O H H CH H H CF₃O H H none none138N R₅ + R₆ = OCH₂O H H CH H H C₆H₅O H H none none 139N R₅ + R₆ =OCH₂CH₂O H H CH H H CF₃O H H none none 140N CH₃O CH₃O H H CH H H CF₃O HH none none 141N R₅ + R₆ = OCH₂CH₂CH₂O H H CH H H CF₃O H H none none142N cyclo CH₃O H H CH H H CF₃O H H none none pentoxy 143N H C₆H₅O H HCH H H CF₃O H H none none 144N CH₃O CH₃O CH₃O H CH H H CF₃O H H nonenone 145N H CF₃O H H CH H H CF₃O H H none none 146N H Benzyl H H CH H HCF₃O H H none none 147N C₆H₅O H H H CH H H R₁₀ + R₁₁= OCH₂CH₂O H nonenone 148N H CF₃O H H CH H H CF₃ H H none none 149N C₆H₅O H H H CH H HCF₃ H H none none 150N C₆H₅ H H H CH H H CF₃ H H none none 151N H C₆H₅ HH CH H H CF₃ H H none none 152N CN H H H CH H H CF₃ H H none none 153N HOCF₃ H H CH H H CF₃ H H none none 154N OCF₃ H H H CH H H H CF₃ H nonenone 155N C₆H₅O H H H CH H H H CF₃ H none none 156N C₆H₅ H H H CH H H HCF₃ H none none 157N H C₆H₅ H H CH H H H CF₃ H none none 158N CN H H HCH H H H CF₃ H none none 159N OCF₃ H H H CH H H H CF₃ H none none 160NCF₃ H H H CH H H H C₆H₅ H none none 161N CF₃ H H H CH H H 3-CF₃— H Hnone none C₆H₅O 162N CF₃ H H H CH H H C₆H₅O H H none none 163N CF₃ H H HCH H H CF₃O H H none none 164N H CF₃ H H CH H H H C₆H₅ H none none 165NH CF₃ H H CH H H 3-CF₃— H H none none C₆H₅O 166N H CF₃ H H CH H H CF₃O HH none none 167N H CF₃ H H CH H H C₆H₅O H H none none 168N CF₃ H CF₃ HCH H H CF₃O H H none none 169N CF₃ H CF₃ H CH H H C₆H₅O H H none none170N CF₃O H H H CH H H CF₃ H CF₃ none none 171N C₆H₅O H H H CH H H CF₃ HCF₃ none none 172N H C₆H₅O H H CH H H C₆H₅O H H none none 173N H CF₃O HH CH H H CF₃O H H none none 174N H CF₃O H H CH H H H C₆H₅O H none none175N C₆H₅O H H H CH H H H C₆H₅O H none none 176N H C₆H₅O H H CH H H HOCF₃ H none none 177N H C₆H₅O H H CH H H H C₆H₅O H none none 178N C₆H₅OH H H CH H H H CN H none none 179N C₆H₅O H H H CH H H CN H H none none180N C₆H₅O H H H CH H H NO₂ H H none none 181N C₆H₅O H H H CH H H H NO₂H none none 182N C₆H₅O H H H CH H H H SO₂CH₃ H none none 183N C₆H₅O H HH CH H H H 2-NO₂4- H none none Cl—C₆H₃O 184N C₆H₅O H H H CH H H4-Cl—C₆H₄O H H none none 185N C₆H₅O H H H CH H H 3,4-Cl—C₆H₃O H H nonenone 186N C₆H₅O H H H CH H H 3-CF₃— H H none none C₆H₃O 187N C₆H₅O H H HCH H H 3,5-Cl—C₆H₃O H H none none 188N C₆H₅O H H H CH H H H CH₃O H nonenone 189N C₆H₅O H H H CH H H H CO₂CH₃ H none none 190N C₆H₅O H H H CH HH 3-CH₃O H H none none C₆H₅O 191N C₆H₅O H H H CH H H 3-CH₃O H H nonenone C₆H₅O 193N C₆H₅O H H H CH H H CO₂CH₃ H H none none 194N CN H H H CHH H OCF₃ H H none none 195N NO₂ H H H CH H H OCF₃ H H none none 196N HCN H H CH H H OCF₃ H H none none 197N H NO₂ H H CH H H OCF₃ H H nonenone 198N SO₂CH₃ H H H CH H H OCF₃ H H none none 199N H SO₂CH₃ H H CH HH OCF₃ H H none none 200N H 4-F—C₆H₅ H H CH H H OCF₃ H H none none SO₂201N SO₂N H H H CH H H OCF₃ H H none none (CH₃)₂ 202N H SO₂N H H CH H HOCF₃ H H none none (CH₃)₂ 203N H CONH₂ H H CH H H OCF₃ H H none none204N H CONH— H H CH H H OCF₃ H H none none C₆H₅ 205N H CO₂CH₃ H H CH H HOCF₃ H H none none 206N H CO₂C₄H₉ H H CH H H OCF₃ H H none none 207N H4-Cl—C₆H₅ H H CH H H C₆H₅O H H none none 208N H 4-CF₃O— H H CH H H CF₃OH H none none C₆H₅ 209N 4-F—C₆H₄O H H H CH H H CF₃O H H none none 210NC₆F₅O H H H CH H H CF₃O H H none none 211N H 4-F—C₆H₅ H H CH H H CF₃O HH none none 212N H 4-CN—C₆H₅ H H CH H H CF₃O H H none none 213N H4-C₆H₅— H H CH H H CF₃O H H none none C₆H₅ 214N C₆H₅O H H H CH CH₃ HCF₃O H H none none 215N C₆H₅O H H H CH CH₃ H NO₂ H H none none 216NC₆H₅O H H H CH CH₃ H H CN H none none 217N C₆H₅O H H H CH 3- H CF₃ H Hnone none CF₃ C₆H₅ 218N C₆H₅O H H H CH C₆H₅ H H C₆H₅ H none none 219NC₆H₅O H H H CH C₆H₅ H CF₃ H H none none 220N C₆H₅O H H H CH CH₃ H F H Hnone none 221N C₆H₅O H H H CH CF₃ H H H H none none 222N bond to —O— ofR₆ aryl group

H H CH H H CF₃O H H none none 223N to CH₂ of R₆ aryl group

H H CH H H CF₃O H H none none 224N C₆H₅O H H H CH H H OCF₂CF₂H H H nonenone 225N 4-Cl—C₆H₅O H H H CH CH H OCF₂CF₂H H H none none 226N 4-F—C₆H₅OH H H CH CH H OCF₂CF₂H H H none none 227N 3,4-Cl— H H H CH H H OCF₂CF₂HH H none none C₆H₅O 228N H C₆H₅ H H CH H H OCF₂CF₂H H H none none 229N H4-Cl—C₆H₅ H H CH H H OCF₂CF₂H H H none none 230N H 4-F—C₆H₅ H H CH H HOCF₂CF₂H H H none none 231N H 4-Br—C₆H₅ H H CH H H OCF₂CF₂H H H nonenone 232N 4-Br—C₆H₅O H H H CH H H OCF₂CF₂H H H none none 233N C₆H₅O H HH CH H H OCF₂CF₃ H H none none 234N 4-Cl—C₆H₅O H H H CH H H OCF₂CF₃ H Hnone none 235N 4-F—C₆H₅O H H H CH H H OCF₂CF₃ H H none none 236N 3,4-Cl—H H H CH H H OCF₂CF₃ H H none none C₆H₅O 237N H C₆H₅ H H CH H H OCF₂CF₃H H none none 238N H 4-Cl—C₆H₅ H H CH H H OCF₂CF₃ H H none none 239N H4-F—C₆H₅ H H CH H H OCF₂CF₃ H H none none 240N H 4-Br—C₆H₅ H H CH H HOCF₂CF₃ H H none none 241N 4-Br—C₆H₅O H H H CH H H OCF₂CF₃ H H none none242N C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 243N 4-Cl—C₆H₅O H H HCH H H OCCl₂CCl₂H H H none none 244N 4-F—C₆H₅O H H H CH H H OCCl₂CCl₂H HH none none 245N 3,4-Cl— H H H CH H H OCCl₂CCl₂H H H none none C₆H₅O246N H C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 247N H 4-Cl—C₆H₅ H H CHH H OCCl₂CCl₂H H H none none 248N H 4-F—C₆H₅ H H CH H H OCCl₂CCl₂H H Hnone none 249N H 4-Br—C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 250N4-Br—C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 251N C₆H₅O H H H CH H HOCCl₂CCl₃ H H none none 252N 4-Cl—C₆H₅O H H H CH H H OCCl₂CCl₃ H H nonenone 253N 4-F—C₆H₅O H H H CH H H OCCl₂CCl₃ H H none none 254N 3,4-Cl— HH H CH H H OCCl₂CCl₃ H H none none C₆H₅O 255N H C₆H₅ H H CH H HOCCl₂CCl₃ H H none none 256N H 4-Cl—C₆H₅ H H CH H H OCCl₂CCl₃ H H nonenone 257N H 4-F—C₆H₅ H H CH H H OCCl₂CCl₃ H H none none 258N H 4-Br—C₆H₅H H CH H H OCCl₂CCl₃ H H none none 259N 4-Br—C₆H₅O H H H CH H HOCCl₂CCl₃ H H none none 260N C₆H₅O H H H CH H H OCCl₂CF₃ H H none none261N 4-Cl—C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 262N 4-F—C₆H₅O H H HCH H H OCCl₂CF₃ H H none none 263N 3,4-Cl— H H H CH H H OCCl₂CF₃ H Hnone none C₆H₅O 264N H C₆H₅ H H CH H H OCCl₂CF₃ H H none none 265N H4-Cl—C₆H₅ H H CH H H OCCl₂CF₃ H H none none 266N H 4-F—C₆H₅ H H CH H HOCCl₂CF₃ H H none none 267N H 4-Br—C₆H₅ H H CH H H OCCl₂CF₃ H H nonenone 268N 4-Br—C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 269N C₆H₅O H HH CH H H OCF₂CCl₃ H H none none 270N 4-Cl—C₆H₅O H H H CH H H OCF₂CCl₃ HH none none 271N 4-F—C₆H₅O H H H CH H H OCF₂CCl₃ H H none none 272N3,4-Cl— H H H CH H H OCF₂CCl₃ H H none none C₆H₅O 273N H C₆H₅ H H CH H HOCF₂CCl₃ H H none none 274N H 4-Cl—C₆H₅ H H CH H H OCF₂CCl₃ H H nonenone 275N H 4-F—C₆H₅ H H CH H H OCF₂CCl₃ H H none none 276N H 4-Br—C₆H₅H H CH H H OCF₂CCl₃ H H none none 277N 4-Br—C₆H₅O H H H CH H H OCF₂CCl₃H H none none 278N C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 279N4-Cl—C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 280N 4-F—C₆H₅O H HH CH H H OCF₂CF₂H OCF₂CF₂H H none none 281N 3,4-Cl— H H H CH H HOCF₂CF₂H OCF₂CF₂H H none none C₆H₅O 282N H C₆H₅ H H CH H H OCF₂CF₂HOCF₂CF₂H 283N H 4-Cl—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 284NH 4-F—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 285N H 4-Br—C₆H₅ H HCH H H OCF₂CF₂H OCF₂CF₂H H none none 286N 4-Br—C₆H₅O H H H CH H HOCF₂CF₂H OCF₂CF₂H H none none 287N C₆H₅O H H H CH H H OCF₃ OCF₃ H nonenone 288N 4-Cl—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 289N 4-F—C₆H₅O HH H CH H H OCF₃ OCF₃ H none none 290N 3,4-Cl— H H H CH H H OCF₃ OCF₃ Hnone none C₆H₅O 291N H C₆H₅ H H CH H H OCF₃ OCF₃ H none none 292N H4-Cl—C₆H₅ H H CH H H OCF₃ OCF₃ H none none 293N H 4-F—C₆H₅ H H CH H HOCF₃ OCF₃ H none none 294N H 4-Br—C₆H₅ H H CH H H OCF₃ OCF₃ H none none295N 4-Br—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 296N C₆H₅O H H H CH HH OCF₂H OCF₂H H none none 297N 4-Cl—C₆H₅O H H H CH H H OCF₂H OCF₂H Hnone none 298N 4-F—C₆H₅O H H H CH H H OCF₂H OCF₂H H none none 299N3,4-Cl— H H H CH H H OCF₂H OCF₂H H none none C₆H₅O 300N H C₆H₅ H H CH HH OCF₂H OCF₂H H none none 301N H 4-Cl—C₆H₅ H H CH H H OCF₂H OCF₂H H nonenone 302N H 4-F—C₆H₅ H H CH H H OCF₂H OCF₂H H none none 303N H 4-Br—C₆H₅H H CH H H OCF₂H OCF₂H H none none 304N 4-Br—C₆H₅O H H H CH H H OCF₂HOCF₂H H none none 305N C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H nonenone 306N 4-Cl—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 307N4-F—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 308N 3,4-Cl— H HH CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none C₆H₅O 309N H C₆H₅ H H CH H HR₁₀ + R₁₁ = OCF₂CF₂O H none none 310N H 4-Cl—C₆H₅ H H CH H H R₁₀ + R₁₁ =OCF₂CF₂O H none none 311N H 4-F—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O Hnone none 312N H 4-Br—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none313N 4-Br—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 314N C₆H₅OH H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 315N 4-Cl—C₆H₅O H H H CHH H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 316N 4-F—C₆H₅O H H H CH H H R₁₀ +R₁₁ = OCCl₂CCl₂O H none none 317N 3,4-Cl— H H H CH H H R₁₀ + R₁₁ =OCCl₂CCl₂O H none none C₆H₅O 318N H C₆H₅ H H CH H H R₁₀ + R₁₁ =OCCl₂CCl₂O H none none 319N H 4-Cl—C₆H₅ H H CH H H R₁₀ + R₁₁ =OCCl₂CCl₂O H none none 320N H 4-F—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂OH none none 321N H 4-Br—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H nonenone 322N 4-Br—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none323N H H H H CH H H OH H H none none 324N H H H H CH H H OH OH H nonenone 325N H H H H CH H H H OH H none none 326N H H H H CH H H OCH₂CF₃ HH none none 327N H H H H CH H H H OCH₂CF₃ H none none 328N H H H H CH HH OCH₂CF₂CF₃ H H none none 329N H H H H CH H H OCH₂CH₂CF₃ H H none none330N H H H H CH H H OCH(CF₃)₃ H H none none 331N H 4-F—C₆H₅O H H CH H HH H H none none 332N 4-F—C₆H₅O H H H CH H H H H H none none 333N Hcyclo- H H CH H H H H H none none hexoxy 334N cyclo-hexoxy H H H CH H HH H H none none 335N H C(CH₃)₃ H H CH H H H H H none none 336N F H H HCH H H

bond to indicated phenyl carbon of R₁₀ subst. H none none

TABLE 5 Structure of “Secondary Phenyl Amine” Reagents (Y and Z eachequal CH; R₇, R₈, R₁₂, R₁₃, R₁₄, and R₁₅ each equal H). (XIII-A)

Reagent Number R₄ R₅ R₆ R₉ R₁₀ R₁₁  1DB H OCF₃ H H OCF₃ H  2DB H Cl H HH CF₃  3DB H Br H H OCF₃ H  4DB H Cl H H OCF₃ H  5DB H Cl H H CF₃ H  6DBH H Cl H CF₃ H  7DB H F H H OCF₃ H  8DB H H Cl H H CF₃  9DB H F H H HCF₃ 10DB H H F H H CF₃ 11DB F H H H H CF₃ 12DB H Cl H CF₃ H H 13DB H HCl CF₃ H H 14DB Cl H H CF₃ H H 15DB H F H CH₃ H H 16DB H H F H H CH₃17DB H F H H CH₃ H 18DB F H H CH₃ H H 19DB H H F H CH₃ H 20DB F H H H HCH₃ 21DB F H H H CF₃ H 22DB Cl H H H CF₃ H 23DB H F H CF₃ H H 24DB H H FCF₃ H H 25DB H F H H CF₃ H 26DB H H F H CF₃ H 27DB H OCF₃ H H H OCF₃

halide, alkyl benzenesulfonate such as a alkyl tosylate, alkyl mesylate,alkyl triflate or similar alkylating reagent of the general structure,

where M is a readily displaceable group such as chloride, bromide,iodide, tosylate, triflate, and mesylate. After allowing the reactionmixture to warm to room temperature, the reaction product is added towater, neutralized if necessary, and extracted with a water-immisciblesolvent such as diethyl ether or methylene chloride. The combinedaprotic solvent extract is washed with saturated brine, dried overdrying agent such as anhydrous MgSO4 and concentrated in vacuo to yieldcrude Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryltertiary omegahydroxyalkylamines”) and Formula V (“Generic SubstitutedPolycyclic Aryl tertiary omegahydroxyalkylamines”), wherein A and Q areindependently aryl and heteroaryl. This material is purified, forexample, by eluting through silica gel with 5-40% of a medium polarsolvent such as ethyl acetate in a non-polar solvent such as hexanes toyield Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryltertiary omegahydroxyalkylamines”) and Formula V (“Generic SubstitutedPolycyclic Aryl tertiary omegahydroxyalkylamines”). Products are testedfor purity by HPLC. If necessary, Formula V-H (“Generic SubstitutedPolycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”) andFormula V (“Generic Substituted Polycyclic Aryl tertiaryomegahydroxyalkylamines”) compounds are purified by additionalchromatography or recrystallization. Products are structurally confirmedby low and high resolution mass spectrometry and NMR. Examples ofspecific Formula V-H (“Generic Substituted Polycyclic Aryl andHeteroaryl tertiary omegahydroxyalkylamines”) and Formula V (“GenericSubstituted Polycyclic Aryl tertiary omegahydroxyalkylamines”) compoundsprepared are summarized in Tables 6 and 7.

TABLE 6 Structure of Substituted Phenyltertiary-omega-Hydroxyalkylamines (Y is CH; R₈, R₉, R₁₂, R₁₃, R₁₄, andR₁₉ are each H; Z is covalent bond and R₁₅ is absent).

Inhibitor Number Column 1 + Column 2 Reagent Reagent R₁ n m R₂ R₃ R₄ R₅R₆ R₇ R₁₀ R₁₁ 1A 1N CF₃ 1 2 H H H C₆H₅O H H OCF₂CF₂H H 1A 2N CF₃ 1 2 H HH OCF₃ H H OCF₂CF₂H H 1A 3N CF₃ 1 2 H H F H H F OCF₂CF₂H H 1A 4N CF₃ 1 2H H H F H H OCF₂CF₂H H 1A 5N CF₃ 1 2 H H H C₆H₅O H H OCF₃ H 1A 6N CF₃ 12 H H H OCF₃ H H OCF₃ H 1A 7N CF₃ 1 2 H H H H phenyl H OCF₃ H 1A 8N CF₃1 2 H H H phenyl H H OCF₃ H 1A 9N CF₃ 1 2 H H H H H H OCF₃ H 1A 10N CF₃1 2 H H H Br H H OCF₃ H 1A 11N CF₃ 1 2 H H H CF₃ F H CF₃ H 1A 12N CF₃ 12 H H H CH₃ H H CF₃ H 1A 13N CF₃ 1 2 H H H CF₃ H H CF₃ H 1A 14N CF₃ 1 2H H H CH₃ H H OCF₃ H 1A 15N CF₃ I 2 H H H F F H OCF₃ H 1A 16N CF₃ 1 2 HH H Br H H CF₃ H 1A 17N CF₃ 1 2 H H H CF₃ F H OCF₃ H 1A 18N CF₃ 1 2 H HH F H H OCF₃ H 1A 19N CF₃ 1 2 H H H Cl H H OCF₃ H 1A 20N CF₃ 1 2 H H H FH H CF₃ H 1A 21N CF₃ 1 2 H H H F F H CF₃ H 1A 22N CF₃ 1 2 H H H Cl H HCF₃ H 1A 23N CF₃ 1 2 H H H F H H phenoxy H 1A 24N CF₃ 1 2 H H H CF₃ Cl HCH₃ H 1A 25N CF₃ 1 2 H H H CF₃ F H CH₃ H 1A 26N CF₃ 1 2 H H H H H H CF₃H 1A 27N CF₃ 1 2 H H F F H H CF₃ H 1A 28N CF₃ 1 2 H H H H OCH₃ H CF₃ H1A 29N CF₃ 1 2 H H H F F H CH₃ H 1A 30N CF₃ 1 2 H H H OCH₃ H H CH₃ H 1A31N CF₃ 1 2 H H H H CH₃ H H H 1A 32N CF₃ 1 2 H H H Cl H H H H 1A 33N CF₃1 2 H H H F H H F H 1A 34N CF₃ 1 2 H H H H OCH₃ H CH₃ H 1A 35N CF₃ 1 2 HH H H H H H H 1A 36N CF₃ 1 2 H H H H CH₃ H CH₃ H 1A 37N CF₃ 1 2 H H H HCl H H H 1A 38N CF₃ 1 2 H H H F H H 3-CF₃- H phenoxy 1A 39N CF₃ 1 2 H HH F H H 4-CH₃O- H phenoxy 1A 40N CF₃ 1 2 H H H F H H 4-Cl- H phenoxy 1A41N CF₃ 1 2 H H H F H H H H 1A 42N CF₃ 1 2 H H H F H H CH₃ H 1A 43N CF₃1 2 H H H F H F CH₃ H 1A 44N CF₃ 1 2 H H F F H H CH₃ H 1A 45N CF₃ 1 2 HH H Cl H H CH₃ H 1A 46N CF₃ 1 2 H H H CH₃ H H CH₃ H 1A 48N CF₃ 1 2 H H HH CH₃ H CF₃ H 1A 51N CF₃ 1 2 H H H H CH₃ H F H 1A 52N CF₃ 1 2 H H H CF₃H H F H 1A 53N CF₃ 1 2 H H H CF₃ H H CH₃ H 1A 54N CF₃ 1 2 H H H OCH₃ H HCF₃ H 1A 56N CF₃ 1 2 H H H H CH₃ H CF₃ H 1A 57N CF₃ 1 2 H H H C₆H₅O H HH OCF₃ 1A 58N CF₃ 1 2 H H H H H H H OCF₃ 1A 59N CF₃ 1 2 H H H OCF₃ H H HOCF₃ 1A 60N CF₃ 1 2 H H H CF₃ F H H CF₃ 1A 61N CF₃ 1 2 H H H H OCH₃ H HCF₃ 1A 62N CF₃ 1 2 H H H CH₃ H H H CF₃ 1A 63N CF₃ 1 2 H H H Cl H H H CF₃1A 64N CF₃ 1 2 H H H CF₃ H H H OCF₃ 1A 65N CF₃ 1 2 H H H F H H H OCF₃ 1A66N CF₃ 1 2 H H H F H F H OCF₃ 1A 67N CF₃ 1 2 H H H Br H H H OCF₃ 1A 68NCF₃ 1 2 H H H Cl H H H OCF₃ 1A 69N CF₃ 1 2 H H H F F H H OCF₃ 1A 70N CF₃1 2 H H H F H H H phenyl 1A 71N CF₃ 1 2 H H H CH₃ H H H OCF₃ 1A 72N CF₃1 2 H H H F F H H CF₃ 1A 73N CF₃ 1 2 H H H Cl H H H CH₃ 1A 74N CF₃ 1 2 HH H OCH₃ H H H CH₃ 1A 75N CF₃ 1 2 H H H F H H H CH₃ 1A 76N CF₃ 1 2 H H FF H H H OCF₃ 1A 78N CF₃ 1 2 H H H H OCH₃ H H CH₃ 1A 79N CF₃ 1 2 H H H HCH₃ H H CH₃ 1A 80N CF₃ 1 2 H H H CH₃ H H H CH₃ 1A 82N CF₃ 1 2 H H H F FH H CH₃ 1A 83N CF₃ 1 2 H H H F H F H CH₃ 1A 84N CF₃ 1 2 H H F F H H HCH₃ 1A 85N CF₃ 1 2 H H F CF₃ H H H CH₃ 1A 86N CF₃ 1 2 H H H H CH₃ H HCF₃ 1A 88N CF₃ 1 2 H H H CF₃ H H H CH₃ 1A 90N CF₃ 1 2 H H H H CF₃ H HCH₃ 1A 92N CF₃ 1 2 H H H CF₃ F H H CH₃

TABLE 7 Structure of Substituted Phenyltertiary-omega-Heteroalkylamines(Z and Y are each CH; R₇, R₈, R₁₂, R₁₃, R₁₄, R₁₅ and R₁₉ are each H).

Inhibitor Number Column 1 + Column 2 Reagent Reagent R₁ n m R₂ R₃ R₄ R₅R₆ R₉ R₁₀ R₁₁ 1A 1DB CF₃ 1 2 H H H OCF₃ H H OCF₃ H 1A 2DB CF₃ 1 2 H H HCl H H H CF₃ 1A 3DB CF₃ 1 2 H H H Br H H OCF₃ H 1A 4DB CF₃ 1 2 H H H ClH H OCF₃ H 1A 5DB CF₃ 1 2 H H H Cl H H CF₃ H 1A 6DB CF₃ 1 2 H H H H Cl HCF₃ H 1A 7DB CF₃ 1 2 H H H F H H OCF₃ H 1A 8DB CF₃ 1 2 H H H H Cl H HCF₃ 1A 9DB CF₃ 1 2 H H H F H H H CF₃ 1A 10DB CF₃ 1 2 H H H H F H H CF₃1A 11DB CF₃ 1 2 H H F H H H H CF₃ 1A 12DB CF₃ 1 2 H H H Cl H CF₃ H H 1A13DB CF₃ 1 2 H H H H Cl CF₃ H H 1A 14DB CF₃ 1 2 H H Cl H H CF₃ H H 1A15DB CF₃ 1 2 H H H F H CH₃ H H 1A 16DB CF₃ 1 2 H H H H F H H CH₃ 1A 17DBCF₃ 1 2 H H H F H H CH₃ H 1A 18DB CF₃ 1 2 H H F H H CH₃ H H 1A 19DB CF₃1 2 H H H H F H CH₃ H 1A 20DB CF₃ 1 2 H H F H H H H CH₃ 1A 21DB CF₃ 1 2H H F H H H CF₃ H 1A 22DB CF₃ 1 2 H H Cl H H H CF₃ H 1A 23DB CF₃ 1 2 H HH F H CF₃ H H 1A 24DB CF₃ 1 2 H H H H F CF₃ H H 1A 25DB CF₃ 1 2 H H H FH H CF₃ H 1A 26DB CF₃ 1 2 H H H H F H CF₃ H 1A 27DB CF₃ 1 2 H H H OCF₃ HH H OCF₃

Compounds of Formula (XXX), which can be used to prepare the “GenericSubstituted Polycyclic Aryl tertiary omegahydroxyalkylamines” compoundsof Tables 6 and 7, are given in Table 2. Reagents 1a and 2a in Table 2are prepared from the corresponding alcohols. The tosylates are readilyobtained by reacting the corresponding alcohol with tosyl chloride usingprocedures found in House's Modern Synthetic Reactions, Chapter 7, W. A.Benjamin, Inc., Shriner, Fuson, and Curtin in The SystematicIndentification of Organic Compounds, 5th Edition, John Wiley & Sons,and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, JohnWiley & Sons, which are incorporated herein by reference.

A preferred procedure for Formula VII (“Generic Substituted PolycyclicAryl tertiary 2-heteroalkylamine”) and Formula VII-H (“GenericSubstituted Polycyclic Heteroaryl tertiary-2-heteroalkylamines”)compounds, wherein the 2-hetero group is a hydroxyl, is Method A ofScheme 2. Oxirane reagents useful in Method A are exemplified, but notlimited to those in Table 1. Formula VII (“Generic SubstitutedPolycyclic Aryl tertiary 2-hydroxyalkylamine”) and Formula VII-H(“Generic Substituted Polycyclic Heteroaryltertiary-2-hydroxyalkylamines”) compounds are prepared by using “GenericSecondary Amine” amines, hydroxylamines, and hydrazines of Formula XIIIprepared above with oxiranes of the type listed in Table 1 andrepresented by the general structure:

In some cases, the oxiranes are prepared by reaction of epoxidationreagents such as MCPBA and similar type reagents readily selectable by aperson of skill-in-the-art with alkenes. Fieser and Fieser in Reagentsfor Organic Synthesis, John Wiley & Sons provides, along with citedreferences, numerous suitable epoxidation reagents and reactionconditions, which are incorporated herein by reference.

Formula VII (“Generic Substituted Polycyclic Aryl tertiary2-heteroalkylamine”) and Formula VII-H (“Generic Substituted PolycyclicHeteroaryl tertiary-2-heteroalkylamines”) compounds, wherein the2-hetero group is an amino, substituted amino, or thiol, can be preparedby using appropriate aziridines and thirranes according to Method A ofScheme 2. Aziridine and thiirane reagents useful in Method A areexemplified, but not limited to those in Table 1. These Formula VII(“Generic Substituted Polycyclic Aryl tertiary 2-heteroalkylamine”) andFormula VII-H (“Generic Substituted Polycyclic Heteroaryltertiary-2-heteroalkylamines”) compounds, wherein the 2-hetero group isan amino, substituted amino, or thiol, can be prepared by using “GenericSecondary Amine” amines, hydroxylamines, and hydrazines of Formula XIIIprepared above with aziridines and thiiranes of the type listed in Table1 and represented by the general structure:

wherein X is selected from N and S and R₁₆ is hydrogen or anothersuitable group when X is N.

TABLE 1 Structure of Oxirane, Aziridine, and Thiirane Reagents. (XX)

Rgnt No. R₁₆ X R₁ R₂ R₃ 1 — O CF₃ H H 2 — O CCl₃ H H 3 — O CF₃ CH₃ H 4 —O CF₃CF₂ H H 5 — O CF₃CF₂CF₂ H H 6 — O CF₃OCF₂CF₂ H H 7 — O CF₃CH₂ H H 8— O CF₃ CHF₂ H 9 — O CF₃ H CF₃ 10 — O CF₃ CF₃ H 11 — O CF₃ C₆H₅ H 12 — OCCl₃ C₆H₅ H 13 — O CCl₃ Cyclopropyl H 14 — O CCl₃ CH₃ H 15 — O CCl₃(CH₃)₂CH H 16 — O CHCl₂ H H 17 — O CHCl₂ Cl H 18 — O CF₃ H CH₃ 19 H NCF₃ CF₃ H 20 H N CF₃ H H 21 Benzyl N CF₃ H H 22 CH₃O N CF₃ H H 23 CH₃ NCF₃ H H 24 Benzyloxy N CF₃ H H 25 — S CF₃ H H 26 — S CF₃CF₂ H H 27 — OCCl₃CH₂ H H 28 — O CBr₃CH₂ H H 29 — O CHBr₂CH₂ H H 30 — O CBrCl₂ H H 31— O CClF₂ H H 32 — O CCl₂F H H 33 — O CCl₃CCl₂ H H 43 — O FCH₂ H H 46 —O CF₃ R₂ + R₃ = (CH₂)₃ 47 — O CF₃ R₂ + R₃ = (CH₂)₄ 48 — O CHF₂ R₂ + R₃ =(CH₂)₄ 56 — O CBrF₂CClFCH₂ H H 57 — O HCF₂CF₂OCH₂ H H

TABLE 2 Structure and Source of Alcohol Reagents. (XXX)

Reagent Number R₁ n M m R₂ R₃ X—R₁₆ Source of Reagent 1A CF₃ 1 OTs 2 H HOH Tosylation of alcohol from Justus Liebigs Ann. Chem. (1969), 720,81-97. 2A CF₃CH₂CH₂ 1 OTs 1 H H OH Tosylation of alcohol from Z.Naturforsch., B: Chem. Sci. (1997), 52 (3). 413-418

A mixture of a “Generic Secondary Amine” amine, hydroxylamine, orhydrazine of Formula XIII and an oxirane of Formula XX are stirred andheated to 40-90° C. for 5 to 48 hours in a tightly capped or containedreaction vessel. A Lewis acid such as ytterbium triflate in acetonitrilemay be added to speed up reaction and improve yield. When a Lewis acidis used, the reaction should be carried out under inert, anhydrousconditions using a blanket of dry nitrogen or argon gas. After coolingto room temperature and testing the reaction mixture for completereaction by thin layer chromatography or high pressure liquidchromatography (hplc), the reaction product is added to water andextracted with a water immiscible solvent such as diethyl ether ormethylene chloride. (Note: If the above analysis indicates that reactionis incomplete, heating should be resumed until complete with theoptional addition of more of the oxirane). The combined aprotic solventextract is washed with saturated brine, dried over drying agent such asanhydrous MgSO₄ and concentrated in vacuo to yield crude Formula VII(“Generic Substituted Polycyclic Aryl tertiary 2-hydroxyalkylamine”) andFormula VII-H (“Generic Substituted Polycyclic Heteroaryltertiary-2-hydroxyalkylamine”) compounds. This material is purified byeluting through silica gel with 5-40% of a medium polar solvent such asethyl acetate in a non-polar solvent such as hexanes to yield theFormula VII (“Generic Substituted Polycyclic Aryl tertiary2-hydroxyalkylamine”) and Formula VII-H (“Generic Substituted PolycyclicHeteroaryl tertiary-2-hydroxyalkylamine”). Products are tested forpurity by HPLC. If necessary, the Formula VII (“Generic SubstitutedPolycyclic Aryl tertiary 2-hydroxyalkylamine”) and Formula VII-H(“Generic Substituted Polycyclic Heteroaryltertiary-2-hydroxyalkylamine”) compounds are purified by additionalchromatography or recrystallization. Products are structurally confirmedby low and high resolution mass spectrometry and NMR. Examples ofspecific Formula VII (“Generic Substituted Polycyclic Aryl ternary2-hydroxyalkylamine”) compounds prepared are summarized in ExampleTables 1 through 54.

Specific Formula VII (“Generic Substituted Polycyclic Aryl tertiary2-heteroalkylamine”) analogs of the “Polycyclic Aryltertiary-2-hydroxyalkylamine” compounds summarized in Example Tables 1through 54, wherein the hydroxyl or oxy group are replaced with anamino, substituted amino, aza, or thiol, can be prepared by using theappropriate aziridine reagents or thiirane reagents readily by adaptingthe procedures in the numerous specific Examples and Schemes disclosedin the present invention. Similarly, intermediates, in which thehydroxyl or oxy group of said intermediates are replaced with an amino,substituted amino, aza, or thiol, can be converted using the numerousspecific Examples and Schemes disclosed in the present invention toother Formula VII (“Generic Substituted Polycyclic Aryl tertiary2-heteroalkylamine”) analogs of the “Polycyclic Aryl tertiary-2-hydroxyalkylamine” compounds.

As summarized in the general Scheme 2 and specific descriptions above,Schemes 5, 6, 7, and 11 illustrate the principles of Scheme 2 for thepreparation of specifically substituted “Generic Substituted PolycyclicAryl Tertiary OmegaHydroxyalkylamines” (V) having 2 aryl groups,“Generic Substituted Polycyclic Aryl and Heteroaryl TertiaryOmegaHydroxyalkylamines” (V-H) having two aromatic substituents made upof 0 to 2 aryl groups and 0 to 2 aromatic heterocyclyl groups, “GenericSubstituted Polycyclic Heteroaryl Tertiary 2-Hydroxyalkylamines” (VII-H)having two aromatic substituents made up of 0 to 2 aryl groups and 0 to2 aromatic heterocyclyl groups, and “Generic Substituted Polycyclic ArylTertiary 2-Hydroxyalkylamines” (VII) having two aryl groups.

Formula VII (“Generic Substituted Polycyclic Aryltertiary-2-hydroxyalkylamines”) and Formula VII-H (“Generic SubstitutedPolycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) can further beprepared in an alternate manner to procedures disclosed above and inSchemes 1 to 7 and 9 to 11. Schemes 45 to 50 detail such procedures toprepare tertiary oxyalkylamine compounds of the present invention byinitial formation of an halogenated, oxygen containing primaryalkylamine XVL (“Generic Substituted Alkylamine”). Said halogenated,oxygen containing primary alkylamine XVL, formed in Schemes 45 and 48,is itself converted to secondary amines, VLX-H (“Heteroaryl Alkyl Amine)and VLX (“Phenyl Alkyl Amine”), using procedures disclosed above.Primary alkylamine XVL is first reacted with an aldehydic or ketoniccarbonyl compound, XI-AH (“Heteroaryl Carbonyl”) and XI-A (“PhenylCarbonyl”) with azeotropic distillation to form imines, VL-H(“Heteroaryl Imine”) and VL (“Phenyl Imine”). Said imines VL-H and VLare then reduced with or without prior isolation by Reduction Methods 1,2 or 3 as disclosed above and in Schemes 1, 3, and 9 to yield secondaryamines, VLX-H (“Heteroaryl Alkyl Amine) and VLX (“Phenyl Alkyl Amine”).Said secondary amine VLX-H can be converted according to Schemes 46 and47 to VII-H (“Generic Substituted Polycyclic Heteroaryl Tertiary2-hydroxyalkylamines”). Using Schemes 49 and 50, VLX can be converted toVII (“Generic Substituted Polycyclic Phenyl Tertiary2-hydroxyalkylamines”). Compounds of this invention in which onearomatic substituent is aryl and the other aromatic substitutent isheteroaryl can be readily prepared by reacting VLX-H with an arylbromide or aralkyl bromide instead of using an heteroaryl bromide orheteroaralkyl bromide as described in Schemes 46 and 47. Similarly,compounds of this invention in which one aromatic substituent is aryland the other aromatic substitutent is heteroaryl can be readilyprepared by reacting VLX with an heteroaryl bromide or heteroaralkylbromide instead of using an aryl bromide or aralkyl bromide as describedin Schemes 49 and 50.

Formula VII (“Generic Substituted Polycyclic Aryltertiary-2-hydroxyalkylamines”) and Formula VII-H (“Generic SubstitutedPolycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) can further beprepared in an alternate manner to procedures disclosed above and inSchemes 1 to 7, 9 to 11, and 45 to 50. Schemes 56,58, and 59 detailalternate procedures to prepare tertiary oxyalkylamine compounds of thepresent invention by initial formation of an halogenated, oxygencontaining secondary alkylamines VLX and VLXX (“Phenyl Alkylamines”) andVLXX-O (“Phenyl Oxy Alkylamines”). Said secondary alkylamines VLX andVLXX (“Phenyl Alkylamines”) and VLXX-O (“Phenyl Oxy Alkylamines”) can beconverted according to Schemes 56, 58 and 59 to VII (“GenericSubstituted Polycyclic Aryl Tertiary 2-hydroxyalkylamines”) and VII-H(“Generic Substituted Polycyclic Heteroaryl Tertiary2-hydroxyalkylamines”) by reaction with appropriate aromatic halidessuch as aryl bromides and heteroaryl bromides as desired.

Formula VII (“Generic Substituted Polycyclic Aryltertiary-2-hydroxyalkylamines”) and Formula VII-H (“Generic SubstitutedPolycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) can further beprepared in an alternate manner to procedures disclosed above and inSchemes 1 to 7, 9 to 11, 45 to 50, 56,58, and 59. Scheme 57 detailsanother alternate procedure to prepare tertiary oxyalkylamine compoundsof the present invention by reacting secondary amines XIII-A (“SecondaryPhenyl Amine”) and XIIIA-H (“Secondary Heteroaryl Amine”) with a diazoester. The intermediate glycinate tertiary amine can then be reduced,partially reoxidized to an aldehyde, and converted using aperfluoroalkyl trimethylsilyl compound (for example,trifluoromethyl-TMS) to the desired product, VII (“Generic SubstitutedPolycyclic Aryl Tertiary 2-hydroxyalkylamines”) and VII-H (“GenericSubstituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylamines”).

Formula V (“Generic Substituted Polycyclic Aryltertiary-3-hydroxyalkylamines”) and Formula V-H (“Generic SubstitutedPolycyclic Heteroaryl tertiary-3-hydroxyalkylamines”), in which thehalogenated oxy containing alkyl side chain has three carbons betweenthe amine and oxy group, can be prepared in a manner similar toprocedures disclosed above and in Schemes 45 to 50. Schemes 30 to 35detail such procedures to prepare tertiary 3-oxyalkylamine compounds ofthe present invention by initial formation of an halogenated, oxygencontaining primary alkylamine XL (“Generic Substituted Alkylamine”).Said halogenated, oxygen containing primary alkylamine XL, formed inSchemes 30 and 33, is itself converted to secondary amines, LX-H(“Heteroaryl Alkyl Amine) and LX (“Phenyl Alkyl Amine”), usingprocedures disclosed above. Primary alkylamine XL is first reacted withan aldehydic or ketonic carbonyl compound, XI-AH (“Heteroaryl Carbonyl”)and XI-A (“Phenyl Carbonyl”) with azeotropic distillation to formimines, L-H (“Heteroaryl Imine”) and L (“Phenyl Imine”). Said imines L-Hand L are then reduced with or without prior isolation by ReductionMethods 1, 2 or 3 as disclosed above and in Schemes 1, 3, and 9 to yieldsecondary amines, LX-H (“Heteroaryl Alkyl Amine) and LX (“Phenyl AlkylAmine”). Said secondary amine LX-H can be converted according to Schemes31 and 32 to V-H (“Generic Substituted Polycyclic Heteroaryl Tertiary3-hydroxyalkylamines”). Using Schemes 34 and 35, LX can be converted toV (“Generic Substituted Polycyclic Phenyl Tertiary3-hydroxyalkylamines”). Compounds of this invention in which onearomatic substituent is aryl and the other aromatic substitutent isheteroaryl can be readily prepared by reacting LX-H with an aryl bromideinstead of using an heteroaryl bromide as described in Schemes 31 and32. Similarly, compounds of this invention in which one aromaticsubstituent is aryl and the other aromatic substitutent is heteroarylcan be readily prepared by reacting LX with an heteroaryl bromideinstead of using an aryl bromide as described in Schemes 34 and 35.

A particularly useful procedure to prepare Formula V-H (“GenericSubstituted Polycyclic Heteroaryl tertiary-3-hydroxyalkylamines”) andVII-H (“Generic Substituted Polycyclic Heteroaryl Tertiary2-hydroxyalkylamines”) compounds of the present invention in which theheteroaryl group is directly bonded is disclosed in Schemes 51 to 54. Anhalogenated, oxygen containing primary alkylamine XVL (“GenericSubstituted Alkylamine”) formed in Schemes 45 and 48 is itself convertedby reaction with LXXI-AH (“Heteroaryl Halide”) to afford secondary amineVLXX-H (“Heteroaryl Secondary Amine) using procedures disclosed inScheme 51 and above. VLXX-H is converted to VII-H (“Generic SubstitutedPolycyclic Phenyl Heteroaryl Tertiary 2-hydroxyalkylamine”) byalkylation chemistry with an aralkyl bromide or aralkyloxyalkyl bromideusing either of two procedures disclosed in Scheme 52. Isolation andpurification is effected as disclosed previously. An halogenated, oxygencontaining primary alkylamine XL (“Generic Substituted Alkylamine”)formed in Schemes 30 and 33 is itself also converted by reaction withLXXI-AH (“Heteroaryl Halide”) to afford secondary amine LXX-H(“Heteroaryl Secondary Amine) using procedures disclosed in Scheme 53and above. LXX-H is converted to V-H (“Generic Substituted PolycyclicPhenyl Heteroaryl Tertiary 3-hydroxyalkylamine”) by alkylation chemistrydisclosed in Scheme 54 and previously and as given above with referenceto Scheme 52. Isolation and purification of V-H and VII-H are effectedas disclosed previously.

Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryltertiary omegahydroxyalkylamines”), Formula V (“Generic SubstitutedPolycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII(“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”),and Formula VII-H (“Generic Substituted Polycyclic Heteroaryltertiary-2-hydroxyalkylamines”) can themselves serve as intermediatesfor conversion to additional compounds of this invention. Compounds ofFormula VII and the present invention useful as intermediates includethose in which the R₇ position substituent in Formula VII (“GenericSubstituted Polycyclic Aryl Tertiary 2-hydroxyalkylamine”) is a bromogroup, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkylgroups, nitro group, amino group, methoxy carbonyl or other alkoxycarbonyl groups, cyano group, or acyl groups. Other preferred compoundsof Formula VII and the present invention useful as intermediates includethose in which the R₁₀ position substituent in Formula VII is a bromogroup, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkylgroups, nitro group, amino group, methoxy carbonyl or other alkoxycarbonyl groups, cyano group, or acyl groups. Other compounds of FormulaVII and the present invention useful as intermediates include those inwhich one or more of R₆, R₇, R₁₁, and R₁₂ substituents in Formula VII isa bromo group, hydroxyl group, sulfhydryl group, bromomethyl or otherbromoalkyl groups, nitro group, amino group, methoxy carbonyl or otheralkoxy carbonyl groups, cyano group, or acyl groups.

Scheme 8 discloses the conversion of a 3-bromo substituent at the R₇position in Formula VII (“Generic Substituted Polycyclic 3-BromoarylTertiary 2-hydroxyalkylamine”) by reaction with a phenol to afford,after isolation and purification as described above for Schemes 2, 5, 6,7, and 11, additional compounds of the present invention of Formula VII(“Generic Substituted Polycyclic 3-Phenoxyaryl Tertiary2-Hydroxyalkylamine”).

Scheme 12-discloses the conversion of a 3-bromo substituent at theR₇-position in Formula VII-H (“Generic Substituted Polycyclic3-Bromoheteroaryl Tertiary 2-hydroxyalkylamine”) by reaction with aphenol to afford, after isolation and purification as described abovefor Schemes 2, 5, 6, 7, and 11, additional compounds of the presentinvention of Formula VII-H (“Generic Substituted Polycyclic3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines”).

Scheme 22 discloses the conversion of a 3-bromo substituent at the R₇position in Formula VII (“Generic Substituted Polycyclic 3-BromoarylTertiary 2-hydroxyalkylamine”) by reaction with an aryl borinate toafford, after isolation and purification as described above for Schemes2, 5, 6, 7, and 11, additional compounds of the present invention ofFormula VII (“Generic Substituted Polycyclic 3-Phenylaryl Tertiary2-Hydroxyalkylamine”).

Scheme 23 discloses the conversion of a 3-bromo substituent at the R₇position in Formula VII (“Generic Substituted Polycyclic 3-BromoarylTertiary 2-hydroxyalkylamine”) by reaction with a primary or secondaryamine to afford, after isolation and purification as described above forSchemes 2, 5, 6, 7, and 11, additional compounds of the presentinvention of Formula VII (“Generic Substituted Polycyclic 3-R₂₂aminoarylTertiary 2-Hydroxyalkylamine”).

Scheme 40 discloses the conversion of a 3-bromo substituent at the R₁₀position in Formula VII (“Generic Substituted Polycyclic 3-BromoarylTertiary 2-hydroxyalkylamine”) by reaction with an aryl borinate toafford, after isolation and purification as described above for Schemes2, 5, 6, 7, and 11, additional compounds of the present invention ofFormula VII (“Generic Substituted Polycyclic 3-Phenylaryl Tertiary2-Hydroxyalkylamine”).

Scheme 41 discloses the conversion of a 3-bromo substituent at the R₁₀position in Formula VII (“Generic Substituted Polycyclic 3-BromoarylTertiary 2-hydroxyalkylamine”) by reaction with a heteroaryl dibutyl tincompound to afford, after isolation and purification as described abovefor Schemes 2, 5, 6, 7, and 11, additional compounds of the presentinvention of Formula VII (“Generic Substituted Polycyclic3-Heteroarylaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 21 discloses the conversion of a 3-bromomethyl substituent at theR₇ position in Formula VII (“Generic Substituted Polycyclic3-Bromomethylaryl Tertiary 2-hydroxyalkylamine”) by reaction with anaryl borinate to afford, after isolation and purification as describedabove for Schemes 2, 5, 6, 7, and 11, additional compounds of thepresent invention of Formula VII (“Generic Substituted Polycyclic3-Arylmethylaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 13 discloses the conversion of a 3-hydroxyl substituent at the R₇position in Formula VII-H (“Generic Substituted Polycyclic3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylamine”) by reaction with anaryl bromide or heteroaryl bromide to afford, after isolation andpurification as described above for Schemes 2, 5, 6, 7, and 11,additional compounds of the present invention of Formula VII-H (“GenericSubstituted Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl,3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary2-Hydroxyalkylamines”).

Scheme 14 discloses the conversion of a 3-hydroxyl substituent at the R₇position in Formula VII (“Generic Substituted Polycyclic 3-HydroxyarylTertiary 2-hydroxyalkylamine”) by reaction with an aryl bromide toafford, after isolation and purification as described above for Schemes2, 5, 6, 7, and 11, additional compounds of the present invention ofFormula VII (“Generic Substituted Polycyclic 3-Phenoxyaryl Tertiary2-Hydroxyalkylamine”).

Scheme 15-discloses the conversion of a 3-hydroxyl substituent at the R₇position in Formula VII-H (“Generic Substituted Polycyclic3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylamine”) by reaction with anaralkyl bromide or heteroaralkyl bromide to afford, after isolation andpurification as described above for Schemes 2, 5, 6, 7, and 11,additional compounds of the present invention of Formula VII-H (“GenericSubstituted Polycyclic 3-Aralkyloxyaryl, 3-Heteroaralkyloxyaryl,3-Heteroaralkyloxyheteroaryl, and 3-Aralkyloxyheteroaryl Tertiary2-Hydroxyalkylamines”).

Scheme 16 discloses the conversion of a 3-hydroxyl substituent at the R₇position in Formula VII (“Generic Substituted Polycyclic 3-HydroxyarylTertiary 2-hydroxyalkylamine”) by reaction with an aralkyl bromide toafford, after isolation and purification as described above for Schemes2, 5, 6, 7, and 11, additional compounds of the present invention ofFormula VII (“Generic Substituted Polycyclic 3-Aralkyloxyaryl Tertiary2-Hydroxyalkylamine”).

Scheme 20 discloses the conversion of a 3-hydroxyl substituent at the R₇position in Formula VII (“Generic Substituted Polycyclic 3-HydroxyarylTertiary 2-hydroxyalkylamine”) by reaction with an R₁₇-bromide toafford, after isolation and purification as described above for Schemes2, 5, 6, 7, and 11, additional compounds of the present invention ofFormula VII (“Generic Substituted Polycyclic 3-R₁₇-oxyaryl Tertiary2-Hydroxyalkylamine”).

Scheme 19 discloses the conversion of a 3-thio substituent at the R₇position in Formula VII (“Generic Substituted Polycyclic 3-thioarylTertiary 2-hydroxyalkylamine”) by reaction with an R₁₇-bromide toafford, after isolation and purification as described above for Schemes2, 5, 6, 7, and 11, additional compounds of the present invention ofFormula VII (“Generic Substituted Polycyclic 3—R₁₇thiaaryl Tertiary2-Hydroxyalkylamine”). “Generic Substituted Polycyclic 3—R₁₇thiaarylTertiary 2-Hydroxyalkylamines” can be oxidized to sulfonyl compounds ofFormula VII (“Generic Substituted Polycyclic 3-R₇sulfonylaryl Tertiary2-Hydroxyalkylamine”).

Scheme 24 discloses the conversion of a 3-nitro substituent at the R₇position in Formula VII (“Generic Substituted Polycyclic 3-NitroarylTertiary 2-hydroxyalkylamine”) by hydrogenation to afford, afterisolation and purification as described above for Schemes 2, 5, 6, 7,and 11, additional compounds of the present invention of Formula VII(“Generic Substituted Polycyclic 3-Aminoaryl Tertiary2-Hydroxyalkylamine”). “Generic Substituted Polycyclic 3-AminoarylTertiary 2-Hydroxyalkylamines” can be acylated to acyl amide compoundsof Formula VII (“Generic Substituted Polycyclic 3-Acylaminoaryl Tertiary2-Hydroxyalkylamine”).

Schemes 25 and 26 disclose the conversion of a 3-amino substituent atthe R₇ position in Formula VII (“Generic Substituted Polycyclic3-Aminoaryl Tertiary 2-hydroxyalkylamine”) by reaction with carbonylcompounds to afford, after isolation and purification as described abovefor Schemes 2, 5, 6, 7, and 11, additional compounds of the presentinvention of Formula VII (“Generic Substituted Polycyclic 3-(SaturatedNitrogen Heterocycl-1yl)aryl Tertiary 2-Hydroxyalkylamine” and “GenericSubstituted Polycyclic 3-(Unsaturated Nitrogen Heterocycl-1yl)arylTertiary 2-Hydroxyalkylamine”, respectively).

Scheme 27 discloses the conversion of a 3-methoxycarbonyl substituent atthe R₇ position in Formula VII (“Generic Substituted Polycyclic3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction withamination reagents to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula VII (“Generic Substituted Polycyclic3-Carboxamidoaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 28 discloses the conversion of a 3-cyano substituent at the R₇position in Formula VII (“Generic Substituted Polycyclic 3-CyanoarylTertiary 2-hydroxyalkylamine”) by reaction with organometallic reagentsto afford, after isolation and purification as described above forSchemes 2, 5, 6, 7, and 11, additional compounds of the presentinvention of Formula VII (“Generic Substituted Polycyclic 3-AcylarylTertiary 2-Hydroxyalkylamine”). Said “Generic Substituted Polycyclic3-Acylaryl Tertiary 2-Hydroxyalkylamines”, according to Scheme 29 can bereduced to hydroxyl compounds of Formula VII (“Generic SubstitutedPolycyclic 3-Hydroxysubstitutedmethylaryl Tertiary2-Hydroxyalkylamine”).

Scheme 36 discloses the conversion of a 3-methoxycarbonyl substituent atthe R₁₀ position in Formula VII (“Generic Substituted Polycyclic3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction withamination reagents to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula VII (“Generic Substituted Polycyclic3-Carboxamidoaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 37 discloses the conversion of a 3-methoxycarbonyl substituent atthe R₁₀ position in Formula VII (“Generic Substituted Polycyclic3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with anorganometallic reagent to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula VII (“Generic Substituted Polycyclic3-(bis-R₂₀-hydroxymethyl)aryl Tertiary 2-Hydroxyalkylamine”).

Scheme 38-discloses the conversion of a 3-methoxycarbonyl substituent atthe R₁₀ position in Formula VII (“Generic Substituted Polycyclic3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction withlithium aluminum hydride to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula VII (“Generic Substituted Polycyclic3-Hydroxymethylaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 39 discloses the conversion of a 3-methoxycarbonyl substituent atthe R₁₀ position in Formula VII (“Generic Substituted Polycyclic3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with analkylation reagent to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula VII (“Generic Substituted Polycyclic3-(bis-R₂₁-hydroxymethyl)aryl Tertiary 2-Hydroxyalkylamine”).

Scheme 55 discloses the conversion of a 3-methoxycarbonyl substituent atthe R₁₀ position in Formula VII (“Generic Substituted Polycyclic3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction intiallywith an amidation reagent and then an R₂₀-organometallic reagent toafford, after isolation and purification as described above for Schemes2, 5, 6, 7, and 11, additional compounds of the present invention ofFormula VII (“Generic Substituted Polycyclic 3-(R₂₀-carbonyl)arylTertiary 2-Hydroxyalkylamine”).

Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryltertiary omegahydroxyalkylamines”), Formula V (“Generic SubstitutedPolycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII(“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”),Formula VII-H (“Generic Substituted Polycyclic Heteroaryltertiary-2-hydroxyalkylamines”) and other compounds of this inventionpossessing hydroxyl, thiol, and amine functional groups can be convertedto a wide variety derivatives. The hydroxyl group X, wherein R₁₆ is ahydrogen, of compounds of Formulas V, V-H, VII, and VII-H can be readilyconverted to esters of carboxylic, sulfonic, carbamic, phosphonic, andphosphoric acids. Acylation to form a carboxylic acid ester is readilyeffected using a suitable acylating reagent such as an aliphatic acidanhydride or acid chloride. The corresponding aryl and heteroaryl acidanhydrides and acid chlorides can also be used. Such reactions aregenerally carried out using an amine catalyst such as pyridine in aninert solvent. In like manner, compounds of Formulas V, V-H, VII, VII-H,and Cyclo-VII that have at least one hydroxyl group present in the formof an alcohol or phenol can be acylated to its corresponding esters.Similarly, carbamic acid esters (urethans) can be obtained by reactingany hydroxyl group with isocyanates and carbamoyl chlorides. Sulfonate,phosphonate, and phosphate esters can be prepared using thecorresponding acid chloride and similar reagents. Compounds of FormulasV, V-H, VII, VII-H, and Cyclo-VII that have at least one thiol grouppresent can be converted to the corresponding thioesters derivativesanalogous to those of alcohols and phenols using the same reagents andcomparable reaction conditions. Compounds of Formulas V, V-H, VII,VII-H, and Cyclo-VII that have at least one primary or secondary aminegroup present can be converted to the corresponding amide derivatives.Amides of carboxylic acids can be prepared using the appropriate acidchloride or anhydrides with reaction conditions analogous to those usedwith alcohols and phenols. Ureas of the corresponding primary orsecondary amine can be prepared using isocyanates directly and carbamoylchlorides in the presence of an acid scavenger such as triethylamine orpyridine. Sulfonamides can be prepared from the corresponding sulfonylchloride in the presence of aqueous sodium hydroxide. Suitableprocedures and methods for preparing these derivatives can be found inHouse's Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner,Fuson, and Curtin in The Systematic Indentification of OrganicCompounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser inReagents for Organic Synthesis, Volume 1, John Wiley & Sons. Reagents ofa wide variety that can be used to derivative hydroxyl, thiol, andamines of compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII areavailable from commerical sources or the references cited above, whichare incorporated herein by reference.

Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryltertiary omegahydroxyalkylamines”), Formula V (“Generic SubstitutedPolycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII(“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”),Formula VII-H (“Generic Substituted Polycyclic Heteroaryltertiary-2-hydroxyalkylamines”) and other compounds of this inventionpossessing hydroxyl, thiol, and amine functional groups can be alkylatedto a wide variety derivatives. The hydroxyl group X, wherein R₁₆ is ahydrogen, of compounds of Formulas V, V-H, VII, and VII-H can be readilyconverted to ethers. Alkylation to form an ether is readily effectedusing a suitable alkylating reagent such as an alkyl bromide, alkyliodide or alkyl sulfonate. The corresponding aralkyl, heteroaralkyl,alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides,iodides, and sulfonates can also be used. Such reactions are generallycarried out using an alkoxide forming reagent such as sodium hydride,potassium t-butoxide, sodium amide, lithium amide, and n-butyl lithiumusing an inert polar solvent such as DMF, DMSO, THF, and similar,comparable solvents, amine catalyst such as pyridine in an inertsolvent. In like manner, compounds of Formulas V, V-H, VII, VII-H, andCyclo-VII that have at least one hydroxyl group present in the form ofan alcohol or phenol can be alkylated to their corresponding ethers.Compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have atleast one thiol group present can be converted to the correspondingthioether derivatives analogous to those of alcohols and phenols usingthe same reagents and comparable reaction conditions. Compounds ofFormulas V, V-H, VII, VII-H, and Cyclo-VII that have at least oneprimary, secondary or tertiary amine group present can be converted tothe corresponding quaternary ammonium derivatives. Quaternary ammoniumderivatives can be prepared using the appropriate bromides, iodides, andsulfonates analogous to those used with alcohols and phenols. Conditionsinvolve reaction of the amine by warming it with the alkylating reagentwith a stoichiometric amount of the amine (i.e., one equivalent with atertiary amine, two with a secondary, and three with a primary). Withprimary and secondary amines, two and one equivalents, respectively, ofan acid scavenger are used concurrently. Tertiary amines can be preparedfrom the corresponding primary or secondary amine by reductivealkylation with aldehydes and ketones using reduction methods 1, 2, or 3as shown in Scheme 3. Suitable procedures and methods for preparingthese derivatives can be found in House's Modern Synthetic Reactions, W.A. Benjamin, Inc., Shriner, Fuson, and Curtin in The SystematicIndentification of Organic Compounds, 5th Edition, John Wiley & Sons,and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, JohnWiley & Sons. Perfluoroalkyl derivatives can be prepared as described byDesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of awide variety that can be used to derivative hydroxyl, thiol, and aminesof compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII are availablefrom commerical sources or the references cited above, which areincorporated herein by reference.

Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryltertiary omegahydroxyalkylamines”), Formula V (“Generic SubstitutedPolycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII(“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”),Formula VII-H (“Generic Substituted Polycyclic Heteroaryltertiary-2-hydroxyalkylamines”) and certain other compounds of thisinvention can be converted, according to Schemes 17 and 18, to thecorresponding cyclic derivatives represented by the general designation“Tricyclic tertiary-oxyalkylamines” exmplified by Formula Cyclo-VII(“Substituted Tricyclic Phenyl tertiary-2-oxyalkylamines”). The hydroxylgroup X, wherein R₁₆ is a hydrogen of compounds of Formulas V, V-H, VII,and VII-H can be cyclized to corresponding cyclic ethers. Compoundssuitable for cyclization will normally have at least one leaving groupwithin 5 to 10 continuous atoms of the hydroxyl group X wherein R₁₆ is ahydrogen. Most preferably the leaving group will be within 5 to 7 atomsof the hydroxyl group X so as to form a 5 to 7 membered ring heteroatomcontaining ring. When the leaving group is part of an aromatic ringsystem, the leaving group will be preferably in an ortho position.Suitable leaving groups generally include halides, sulfates, sulfonates,trisubsituted amino, disubstituted sulfonium, diazonium, and like, and,in the case of aromatic systems, also includes nitro, alkoxy, aryloxy,heteroaryloxy, and alkylthio. When X—R₁₆ is a thiol, amino, orsubstituted amino, the corresponding analogous sulfur and nitrogenanalogs, Cyclo-VII (“Substituted Tricyclic Phenyltertiary-2-thioalkylamines and tertiary-2-azaalkylamines”), of FormulaCyclo-VII (“Substituted Tricyclic Phenyl tertiary-2-oxyalkylamines”) canbe obtained.

The cyclization reaction to form “Tricyclic tertiary-oxyalkylamines” canbe accomplished by aromatic and aliphatic nucleophilic substitutionreactions such as those disclosed in March's Advanced Organic Chemistry,4th Edition, John Wiley & Sons, especially at pages 293-412 and 649-658and the references cited therein, which are incorporated herein byreference. Hydroxyl containing suitably substituted compounds can beconverted to a cyclic analog by heating a suitably substituted compoundunder anhydrous conditions in a suitable solvent, such asdimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetraglyme,or hexamethylphosphoramide, in the presence of a suitable base such aspotassium carbonate, cesium carbonate, sodium hydroxide, potassiumtertiary-butoxide, or lithium diisopropylamide. Alternately, sodiumamide in anhydrous ammonia solvent can be used. Temperatures in therange of −20° C. to 200° C. can be used for time periods of 30-minutesto more than 24 hours. The preferred temperature can be selected bystandard synthetic chemical technique balancing maximum yield, maximumpurity, cost, ease of isolation and operation, and time required.Isolation of the “Tricyclic tertiary-oxyalkylamines” can be effected asdescribed above for other tertiary-oxyalkylamines. Representative“Tricyclic tertiary-oxyalkylamines” prepared using the methodologydescribed above are included in Table 8.

The following examples are provided to illustrate the present inventionand are not intended to limit the scope thereof. Those skilled in theart will readily understand that known variations of the conditions andprocesses of the following preparative procedures can be used to preparethese compounds.

TABLE 8 Structure of Substituted Tricyclictertiary-2-oxyalkylamines

Y Z R₅ K₁—R₆ R₁₀ K₂—R₁₁ R₁₂ R₁₃ CH₂ — 4-chloro-3-ethylphenoxy C—H HC—CF₃ H H CH₂ — 4-chloro-3-ethylphenoxy N H C—CF₃ H H CH₂ —4-chloro-3-ethylphenoxy C—H H C—H CF₃ H CH₂ — 4-chloro-3-ethylphenoxy NH C—H CF₃ H CH₂ — 4-chloro-3-ethylphenoxy C—H H N CF₃ H — —4-chloro-3-ethylphenoxy C—H H C—CF₃ H H — — 4-chloro-3-ethylphenoxy N HC—CF₃ H H — — 4-chloro-3-ethylphenoxy C—H H C—H CF₃ H — —4-chloro-3-ethylphenoxy N H C—H CF₃ H — — 4-chloro-3-ethylphenoxy C—H HN CF₃ H

Y Z R₇ K₁—R₆ R₁₀ K₂—R₁₁ R₅ R₈ CH₂ — 4-chloro-3-ethylphenoxy C—H OCF₂CF₂HC—H H H CH₂ — 4-chloro-3-ethylphenoxy N OCF₂CF₂H C—H H H CH₂ —4-chloro-3-ethylphenoxy C—H OCF₂CF₂H N H H CH₂ — phenoxy C—H OCF₂CF₂HC—H H H CH₂ — phenoxy N OCF₂CF₂H C—H H H CH₂ — phenoxy C—H OCF₂CF₂H N HH CH₂ — 4-chloro-3-ethylphenoxy C—H CF₂CF₃ C—H H H CH₂ —4-chloro-3-ethylphenoxy N CF₂CF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxyC—H CF₂CF₃ N H H CH₂ — phenoxy C—H CF₂CF₃ C—H H H CH₂ — phenoxy N CF₂CF₃C—H H H CH₂ — phenoxy C—H CF₂CF₃ N H H CH₂ — 4-chloro-3-ethylphenoxy C—HCF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxy N CF₃ C—H H H CH₂ —4-chloro-3-ethylphenoxy C—H CF₃ N H H CH₂ — phenoxy C—H CF₃ C—H H H CH₂— phenoxy N CF₃ C—H H H CH₂ — phenoxy C—H CF₃ N H H CH₂ —4-chloro-3-ethylphenoxy C—H OCF₂CF₂H C—H H F CH₂ —4-chloro-3-ethylphenoxy N OCF₂CF₂H C—H H F CH₂ — 4-chloro-3-ethylphenoxyC—H OCF₂CF₂H N H F CH₂ — 4-chloro-3-ethylphenoxy C—H 2-furyl C—H H H CH₂— 4-chloro-3-ethylphenoxy N 2-furyl C—H H H CH₂ —4-chloro-3-ethylphenoxy C—H 2-furyl N H H CH₂ — 4-chloro-3-ethylphenoxyC—H SCF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxy N SCF₃ C—H H H

R₂₂ is selected independently from any one or two of the followinggroups: hydrido, hydroxy, aryloxy, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, alkoxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkoxy,halocycloalkoxyalkyl, arylsulfinylalkyl, arylsulfonylalkyl, alkylaminocycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, hydroxyalkyl, amino, alkoxy, alkylsulfonylalkyl,aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl,alkenyloxyalkyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,heteroaryl, halocycloalkenyloxyalkyl, heteroarylalkyl, halocycloalkenyl,and heteroarylthioalkyl.

R₂₂ is selected independently from any one or two of the followinggroups: hydrido, hydroxy, aryloxy, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, alkoxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkoxy,halocycloalkoxyalkyl, heteroaryl, arylsulfinylalkyl, arylsulfonylalkyl,alkylamino cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, hydroxyalkyl, amino, alkoxy, alkylsulfonylalkyl,aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl,alkenyloxyalkyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkenyl,halocycloalkenyloxyalkyl, heteroarylalkyl, andheteroarylthioalkyl.

R₁₇ is selected from alkyl, alkenyl, alkynyl, aryl, aryloxyalkyl,aralkoxyalkyl, aralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,heteroaryl, heteroarylalkyl, heteroarylthioalkyl,heteroaralkylthioalkyl, heteroaralkylthioalkyl,alkoxyalkyl,cycloalkenylalkyl, arylthioalkyl, aralkyl, and cycloalkenyl.

R₁₇ is selected from alkyl, alkenyl, alkynyl, aryl, aryloxyalkyl,aralkoxyalkyl, aralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,heteroaryl, heteroarylalkyl, heteroarylthioalkyl, aralkyl,heteroaralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,cycloalkenylalkyl, arylthioalkyl, and cycloalkenyl.

R₂₀ is selected from alkyl, alkenyl, alkynyl, aryloxyalkyl,aralkoxyalkyl, aralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,aryl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,heteroaralkylthioalkyl, cycloalkenylalkyl, arylthioalkyl, aralkyl,alkoxyalkyl, alkylthioalkyl, and cycloalkenyl.

R₂₁ is selected from perfluoroalkyl, perfluoroalkenyl,perfluorocycloalkyl, perfluorocycloalkylalkyl, perfluoroaralkyl,perfluoroalkoxyalkyl,

R₂₀ is selected from alkyl, alkenyl, alkynyl, aryl, aryloxyalkyl,aralkoxyalkyl, aralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,heteroaryl, heteroarylalkyl, heteroarylthioalkyl,heteroaralkylthioalkyl, heteroaralkylthioalkyl, cycloalkenylalkyl,arylthioalkyl, aralkyl, alkoxyalkyl,and cycloalkenyl.

NOTE: Heteroaryl Analogs Can Be Prepared Using Heteroaryl Analogs ofX-A, VLX, and XI-A.

The following examples are provided to illustrate the present inventionand are not intended to limit the scope thereof. Without furtherelaboration, it is believed that one skilled in the art can, using thepreceding descriptions, utilize the present invention to its fullestextent. Therefore the following preferred specific embodiments are to beconstrued as merely illustrative and not limitative of the remainder ofthe disclosure in any way whatsoever. Compounds containing multiplevariations of the structural modifications illustrated in the precedingschemes or the following Examples are also contemplated. Those skilledin the art will readily understand that known variations of theconditions and processes of the following preparative procedures can beused to prepare these compounds.

One skilled in the art may use these generic methods to prepare thefollowing specific examples, which have been or may be properlycharacterized by ¹H NMR and mass spectrometry. These compounds also maybe formed in vivo.

The following examples contain detailed descriptions of the methods ofpreparation of compounds of Formula V-H. These detailed descriptionsfall within the scope and are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are Degrees centigrade unlessotherwise indicated.

EXAMPLE 1

3-[(3-fluorophenyl)-[[3-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-1A) A solution of 3-fluoroaniline (1.92-mL, 0.02 mol) andtrifluoro-m-tolualde-hyde (2.68 mL, 0.02 mol) in 30 mL of cyclohexanewas refluxed using a Dean-Stark trap to remove water. After 4 hours, thecyclohexane was removed in vacuo to yield 5.4 g (100%) of the desiredimine product as an amber oil. MS m/z=267 [M⁺]. ¹H NMR (CDCl₃) δ8.50 (s,1H), 8.22 (s, 1H), 8.09 (d, 1H), 7.78 (d, 1H), 7.63 (t, 1H), 7.39 (dq,1H), 6.99 (m, 3H). This imine (5.34 g, 0.02 mol) was then slurried in 30mL of methanol at 0° C. Solid NaBH₄ (1.32 g, 0.0349 mol) was added inbatches over 3 minutes at 0° C. The reaction was stirred below 10° C.for 30 minutes and then warmed gradually to 15° C. After 1 hour, thesolution was cooled, and 3% aq. HCl solution was added until the aqueouslayer was acidic. The aqueous solution was extracted twice with diethylether. The combined ether extracts were washed 3 times with brine, dried(MgSO₄), and concentrated in vacuo to yield 4.45 g (82%) of the desiredN-(3-fluorophenyl)-[[3-(trifluoromethyl)phenyl]methyl]amine product as alight amber oil. MS m/z=269 [M⁺]. ¹H NMR (CDCl₃) δ7.57 (m, 4H), 7.14(dq, 1H), 6.45 (m, 2H), 6.33 (dt,1H), 4.41 (s, 2H), 4.27 (br, 1H).

The amine product EX-1A (2.69 g, 0.01 mol) was mixed with3,3,3-trifluoro-1,2-epoxypropane (1.34 g, 0.012 mol), and the mixturewas heated to 90° C. for 40 hours in a tightly capped vessel. Aftercooling to room temperature, the reaction product was purified byeluting through silica gel with 10% ethyl acetate in hexanes to yield2.54 g (67%) of the desired aminopropanol as a light yellow oil, 100%pure product by GC and reverse phase HPLC. HRMS calcd. for C₁₇H₁₄F₇NO:382.1042 [M+H]⁺, found: 382.1032. ¹H NMR (CDCl₃) δ7.47 (m, 4H), 7.19 (q,1H), 6.50 (m, 3H), 4.50 (ABq, 2H), 4.39 (m,1H), 3.93 (dd, 1H), 3.60 (dd,1H), 2.51 (d, 1H).

Additional substituted 3-[(N-aryl)-[[aryl]methyl]amino]-halo-2-propanolscan be prepared by one skilled in the art using similar methods, asshown in Example Tables 1, 43, 46, and 47. Substituted3-[(N-aralkyl)-[[aralkyl]amino]-halo-2-propanols can also be prepared byone skilled in the art using similar methods, as shown in Example Tables2, 3, 44, and 45. Substituted3-[(N-aryl)[[aralkyl]amino]-halo-2-propanols can be prepared by oneskilled in the art using similar methods, as shown in Example Table 4.Substituted 3-[(N-aryl orN-aralkyl)-[[aryl]methyl]amino]-haloalkoxy-2-propanols can be preparedby one skilled in the art using similar methods, as shown in ExampleTables 5 and 48.

EXAMPLE TABLE 1 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols

Calc.* Obs.* Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M⁺] [M⁺]  2 H H295.1184 295.1180  3 3-OCH₃ 3-CH₃ 339.1446 339.1449  4 3-OCH₃ 4-CH₃339.1446 339.1444  5 4-CH₃ 3-CH₃ 323.1497 323.1491  6 4-OCH₃ 4-CH₃339.1446 339.1440  7 4-Cl H 329.0794 329.0783  8 4-CH₃ 4-CH₃ 323.1497323.1495  9 3-Cl 3-CH₃ 343.0951 343.0950 10 3-F H 313.1090 313.1086 113-CH₃ 3-CH₃ 323.1497 323.1509 12 3-CH₃ 4-CH₃ 323.1497 323.1504 13 2-CH₃4-CH₃ 323.1497 323.1483 14 4-CH₃ H 309.1340 309.1331 15 2-CH₃ H 309.1340309.1337 16 3-Cl H 329.0794 329.0794 17 3-F, 4-F 3-CH₃ 345.1152 345.114318 3-F 3-F 331.0996 331.0984 19 3-F, 4-F 3-CF₃ 399.0869 399.0827 204-CH₃ 3-CF₃ 377.1214 377.1180 21 2-CH₃ 3-CF₃ 377.1214 377.1176 22 3-F,4-F 4-CF₃ 399.0869 399.0822 23 4-OCH₃ 4-CF₃ 393.1163 393.1159 24 3-F,4-F 4-CH₃ 345.1152 345.1136 25 3-CH₃ 3-CF₃ 377.1214 377.1231 26 3-OCH₃4-CF₃ 393.1163 393.1179 27 2-CH₃ 3-CH₃ 323.1497 323.1486 28 4-OCH₃ 3-CH₃339.1446 339.1435 29 3-F, 5-F 4-CH₃ 345.1152 345.1159 30 3-Br 3-CF₃441.0163 441.0135 31 3-F 3-OCF₃ 397.0913 397.0894 32 4-CH₃ 3-F 327.1246327.1291 33 3-F 4-CH₃ 328.1324 328.1333 34 3-Cl 4-CH₃ 344.1029 345.104535 H 3-CF₃ 364.1136 364.1122 36 3-Br 3-OCF₃ 458.0190 458.0145 37 4-CH₃4-CF₃ 378.1292 378.1259 38 3-Cl 3-CF₃ 398.0746 398.0727 39 3-CH₃ 4-CF₃378.1292 378.1274 40 2-CH₃ 4-CF₃ 378.1292 378.1259 41 3-Cl 3-OCF₃414.0695 414.0699 42 3-CF₃ 3-OCF₃ 448.0959 448.0961 43 3-F 3-OCF₂CF₂H430.1053 430.1042 44 3-I 3-OCF₂CF₂H 538.0114 538.0077 45 3-CF₃ 4-CH₃378.1292 378.1296 46 3-CF₃ 3-F 382.1042 382.1073 47 3-CF₃ 3-CF₃ 432.1010432.1026 48 3-OCH₃ 3-CF₃ 394.1241 394.1227 49 3-F 3-CH₃ 328.1324328.1300 50 3-Cl 4-CF₃ 398.0746 398.0731 51 4-OCH₃ 3-CF₃ 394.1241394.1237 52 3-CF₃, 4-F 3-CF₃ 450.0915 450.0913 53 3-CF₃, 4-F 4-CH₃396.1198 396.1179 54 3-CF₃ 4-OCF₃ 448.0959 448.0967 55 3-Cl 4-OCF₃414.0695 414.0690 56 3-F, 4-F 4-OCF₃ 416.0886 416.0904 57 3-F 4-OCF₃398.0991 398.0975 58 3-CF₃, 4-F 3-CH₃ 396.1197 396.1178 59 H 4-OCF₃380.1085 380.1077 60 3-OCF₃ 4-OCF₃ 464.0908 464.0877 61 3-CH₃ 4-OCF₃394.1241 394.1248 62 3-Br 4-OCF₃ 458.0189 458.0189 63 3-phenoxy 4-OCF₃472.1347 472.1344 64 3-F 3-phenoxy 406.1430 406.1418 65 3-F 4-phenyl390.1481 390.1468 66 3-phenyl 3-OCF₃ 456.1397 456.1395 67 3-CF₃, 4-Cl3-CH₃ 412.0903 412.0892 68 3-F, 5-F 4-OCF₃ 416.0896 416.0895 69 2-F, 3-F3-CF₃ 400.0941 416.0956 70 2-F, 5-F 3-OCF₂CF₂H 448.0959 448.0940 713-OCF₃ 3-OCF₂CF₂H 496.0971 496.0959 72 3-CH₃ 3-OCF₃ 394.1241 394.1244 73H 3-OCF₃ 380.1085 380.1075 74 3-OCF₃ 3-OCF₃ 464.0908 464.0898 75 3-CF₃,4-F 4-CF₃ 450.0915 450.0906 76 3,4-(CH═CH)₂— 3-OCF₃ 430.1241 430.1253 773-phenoxy 3-OCF₃ 472.1347 472.1342 78 3-F, 4-F 3-OCF₃ 416.0896 416.088479 4-phenyl 3-OCF₃ 456.1398 456.1368 80 2-F, 3-F 4-OCF₃ 416.0897416.0885 81 3-F, 5-F 3-CH₃ 346.1230 346.1246 82 3-OCF₃ 3-phenoxy472.1347 472.1342 83 3-OCF₃ 3-benzyloxy 486.1504 486.1503 84 3-phenoxy3-phenoxy 480.1786 480.1772 85 2-phenyl 3-phenoxy 464.1837 464.1821 864-phenyl 3-phenoxy 464.1837 464.1836 87 4-phenyl 3-OCF₂CF₂H 488.1460488.1443 88 4-n-octyl 3-OCF₃ 492.2337 492.2341 89 3,4-(OCF₂CF₂O) 3-OCF₃510.0763 510.0747 90 4-F 3-OCF₃ 398.0991 398.1023 91 3-phenoxy 3-ethoxy432.1787 432.1770 92 3-phenoxy 3-(4-Cl-phenoxy) 514.1397 514.1426 933-OCF₃ 3-(4-Cl-phenoxy) 506.0958 506.0971 94 3-phenoxy 3-(3,4-Cl₂—C₆H₃O)548.1007 548.1002 95 3-OCF₃ 3-(3,4-Cl₂—C₆H₃O) 540.0568 540.0555 963-OCF₃ 3-(3,5-Cl₂—C₆H₃O) 540.0568 540.0568 97 3-OCF₃ 4-OCH₃ 502.1453502.1466 98 3-OCF₃ 3-CF₃ 540.1221 540.1248 99 3-OCF₃ 3-benzyloxy,516.161  516.1626 4-OCH₃ 100  3-OCF₃ 3,4-dibenzyloxy 592.1922 592.1915101  3-OCF₃ 3-OCH₂CH₃ 424.1347 424.1331 102  3-OCF₃ 3-acetoxy 438.114 438.1142 103  3-OCF₃ 3-(2-OH-ethoxy) 440.1297 440.1302 104  3-OCF₃3-[(3-Cl, 2-OH)- 488.1063 488.1050 n-propoxy] 105  3-OCF₃ 3,4-(OCH₂CH₂O)438.114  438.1142 106  3-OCF₃ 4-benzyloxy, 516.1609 516.1608 3-OCH₃ 107 3-OCF₃ 3,5-dibenzyloxy 592.1922 592.1903 108  3-CF₃ 3-(3-CF₃-phenoxy)524.1372 524.1281 109  3-CF₃ 3-phenoxy 456.1398 456.1421 110  4-CF₃3-(3-CF₃-phenoxy) 524.1272 524.1259 111  4-CF₃ 3-phenoxy 456.1398456.1415 112  4-CF₃ 3-OCF₃ 424.1347 424.1331 113  3-phenoxy 3-nitro433.1375 433.1379 114  3-phenoxy 3-(3,5-Cl₂—C₆H₃O) 548.1007 548.1016115  3-phenoxy 3-(3-CF₃-phenoxy) 548.166  548.1639 116  3-OCF₃3,4-dimethoxy 440.1296 420.1294 117  3-OCF₃ 3-OCH₂CH₃, 454.1453 454.14584-OCH₃ 118  3-OCF₃ 3,4-diacetoxy 496.1194 496.1183 119  3-OCF₃4-acetoxy, 3-OCH₃ 468.1245 468.1239 120  3-OCF₃ 4-n-butoxy 452.1584452.1614 121  3-OCF₃ 3-OCH₃ 410.1191 410.1179 122  3-OCF₃ 4-OCH₃410.1191 410.1177 123  3-OCH₃ 3-OCH₃ 356.1473 356.1469 124  3-OCH₃3-OCF₃ 410.1191 410.1158 125  3-OCF₃ 4-n-propoxy 438.1503 438.1517 126 3-benzyloxy 3-OCF₃ 486.1504 486.1524 127  3-benzyloxy 3-phenoxy 494.1947494.1956 128  3-ethoxy 3-OCF₃ 424.1347 424.1363 129  3,4-(OCH₂O) 3-OCF₃424.0983 424.0990 130  3,4-(OCH₂O) 3-phenoxy 432.1424 432.1432 131 3,4-(O(CH₂)₂O) 3-OCF₃ 438.1140 438.1165 132  3,4-dimethoxy 3-OCF₃440.1296 440.1319 133  4-phenoxy 3-OCF₃ 472.1347 472.1334 134  4-OCF₃3-OCF₃ 464.0908 464.0923 135  4-n-butoxy 3-OCF₃ 452.1660 452.1624 136 4-benzyl 3-OCF₃ 470.1554 470.1148 137  3-phenoxy 3,4-(OCH₂CH₂O) 446.1579446.1583 138  3-OCF₃ 3,4-diethoxy 468.1609 468.1638 139  3,4-(O(CH₂)₃O)3-OCF₃ 452.1297 452.1307 140  3-OCF₃ 4-CF₃ 448.0959 448.0985 141 4-phenyl 4-CF₃ 440.1449 440.1451 142  3-cyano 4-CF₃ 389.1089 389.1097143  3-CF₃ 4-phenyl 440.1449 440.1444 144  4-CF₃ 4-phenyl 440.1449440.1457 145  3-phenoxy 3-CF₃, 5-CF₃ 524.1272 524.1285 146  3-phenoxy4-cyano 413.1477 413.149  147  3-phenoxy 3-cyano 413.1477 413.1493 148 3-phenoxy 4-nitro 433.1375 433.1398 149  3-phenoxy 3-CF₃ 456.1398456.1414 150  3-phenoxy 4-CF₃ 456.1398 456.1394 151  4-phenoxy 3-phenoxy480.1786 480.1794 152  3-OCF₃ 4-phenoxy 472.1347 472.1347 153  3-phenoxy4-phenoxy 480.1786 480.1780 154  4-phenoxy 4-phenoxy 480.1786 480.1298155  4-phenoxy 4-OCF₃ 472.1347 472.1338 156  3-phenoxy 4-SO₂CH₃ 466.1298466.1253 157  3-phenoxy 4-CO₂CH₃ 446.1579 446.1569 158  3-OCF₃ 4-ethoxy424.1347 424.1317 159  3-cyclopentoxy 3-OCF₃ 494.1766 494.1771 4-methoxy160  3,4,5-trimethoxy 3-OCF₃ 470.1402 470.1408 161  3-phenoxy3-(OC₆H₄-4-OCH₃) 510.1892 510.1881 162  3-cyano 3-OCF₃ 405.1038 405.1021163  4-cyano 3-OCF₃ 405.1038 405.104  164  4-CO₂-n-C₄H₉ 3-OCF₃ 480.161 480.1594 165  4-(4-Cl-phenoxy) 3-phenoxy 514.1397 514.1407 166 3-(4-F-phenoxy) 3-OCF₃ 490.1253 490.1211 167  4-(4-CN—C₆H₄) 3-OCF₃481.135  481.1354 168  3-phenoxy 4-(OC₆H₄-4-OCH₃) 510.1892 510.1919*Note: Calculated (Calc.) and Observed (Obs.) masses measured forExample Numbers 33 through 168 are [M + H]⁺.

Example Table 2. 3-[N-[(aryl)methyl]-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols

Ex. Calc.* Obs.* No. R_(SUB1) R_(SUB2) Mass [M⁺] Mass [M⁺] 169 3-F 4-CF₃395.1120 395.1107 170 4-F 4-CF₃ 395.1120 395.1113 171 2-F 4-CF₃ 395.1120395.1102 172 3-Cl 4-CF₃ 411.0825 411.0779 173 4-Cl 4-CF₃ 411.0825411.0756 174 2-Cl 4-CF₃ 411.0825 411.0779 175 3-Cl 2-CF₃ 411.0825411.0753 176 4-Cl 2-CF₃ 411.0825 411.0754 177 2-Cl 2-CF₃ 411.0825411.0760 178 3-F 4-CH₃ 341.1403 341.1384 179 4-F 4-CH₃ 341.1403 341.1369180 3-F 3-CH₃ 341.1403 341.1372 181 2-F 4-CH₃ 341.1403 341.1391 182 4-F3-CH₃ 341.1403 341.1365 183 2-F 3-CH₃ 341.1403 341.1359 184 2-F 3-CF₃395.1120 395.1094 185 3-Cl 3-CF₃ 411.0825 411.0767 186 4-Cl 3-CF₃411.0825 411.0770 187 2-Cl 3-CF₃ 411.0825 411.0759 188 3-F 2-CF₃395.1120 395.1071 189 4-F 2-CF₃ 395.1120 395.1119 190 3-F 3-CF₃ 395.1120395.1096 191 4-F 3-CF₃ 395.1120 395.1124 192 3-OCF₃ 3-OCF₃ 478.1064478.0157 193 3-Cl 3-OCF₃ 428.0852 428.0878 194 3-Br 3-OCF₃ 472.0346472.0366 195 3-phenoxy 3-OCF₃ 486.1503 486.1507 196 4-phenyl 3-OCF₃470.1554 470.1566 197 3-nitro 3-OCF₃ 439.1092 439.1051 *Note: Calculated(Calc.) and Observed (Obs.) masses measured for Example Numbers 192through 197 are (M + H]⁺.

Example Table 3. 3-[N-(aralkyl)-N-(aralkyl)amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H]198 2-(3-F-phenyl)- 3-(OCF₂CF₂H)- 458.1364 458.1384 ethyl benzyl

Example Table 4. 3-[N-(aryl)-N-(aralkyl)amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H]199 3-F-phenyl 2- 402.1481 402.1501 fluorenylmethyl 200 3-F-phenyl1-(4-OCH₃- 390.1430 390.1415 naphthyl)methyl 201 2-fluorenyl3-OCF₃-benzyl 468.1398 468.1375 202 3-phenoxyphenyl 1-(4-CN- 427.1633427.1627 phenyl)-ethyl 203 3-phenoxyphenyl 1-(3-F-phenyl)- 420.1587420.1584 ethyl 204 2-(7-bromo- 3-OCF₃-benzyl 546.0503 546.0531fluorenyl) 205 3-phenoxyphenyl 1-(3-nitro- 447.1531 447.1554phenyl)ethyl 206 3-phenoxyphenyl 1-(3-OCF₃- 486.1503 486.151 phenyl)ethyl 207 3-dibenzofuryl 3-(OCF₂CF₂H) 502.1253 502.1241 benzyl

Example Table 5. 3-[N-(aryl or aralkyl)-N-(aralkyl)amino]-1-haloalkoxy-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H]208 3-OCF₃-benzyl 3-OCF₃ 540.1232 540.1219 209 3-OCF₃-phenyl 3-OCF₃526.1076 526.1049 210 3-phenoxy-phenyl 3-OCF₃ 534.1473 534.1515 2113-phenoxy-phenyl isopropoxy 508.2111 508.2112 212 3-phenoxy-phenyl 3-566.1577 566.1604 OCF₂CF₂H 213 3-phenoxy-phenyl 3-ethoxy 494.1954494.1982

EXAMPLE 214

3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-214A) A solution of 3-(phenoxy)aniline (2.78 g, 15 mmol) and3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (3.33 g, 15 mmol) was preparedin 60 mL of dichloroethane. Acetic acid (0.92 mL, 16.05 mmol) and solidNaBH(OAc)₃ (4.13 g, 19.5 mmol) were added. The mixture was stirred atroom temperature for 3 hours, then acidified with 1 N aqueous HCl. Afterneutializing to pH 7.5 with 2.5 N sodium hydroxide, the mixture wasextracted with methylene chloride. The organic layer was washed withbrine and water, then dried over anhydrous MgSO₄, and evaporated to give5.00 g (85%) of the desiredN-(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amineproduct as a brown oil, which was greater than 90% pure by reverse phaseHPLC analysis. MS m/z=391.

Amine product EX-214A (3.13 g, 8 mmol) and3,3,3-trifluoromethyl-1,2-epoxypropane (1.34 g, 12 mmol) were dissolvedin 1.5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate(0.25 g, 0.4 mmol) was added, and the stirred solution was warmed to 50°C., for 1 hour under an atmosphere of nitrogen, at which time HPLCanalysis indicated that no secondary amine starting material remained.The reaction was quenched with water and extracted with ether. The etherlayer was washed with water and brine, then dried over MgSO₄. The crudeproduct was purified by flash column chromatography on silica geleluting with ethyl acetate:hexane (1:16) to give 2.85 g (71%) of thedesired aminopropanol product as a light amber oil, 99% pure by HPLCanalysis. ¹H NMR (CDCl₃) δ7.30 (m, 3H), 7.27 (t, 1H), 7.20 (m, 3H), 7.02(s, 1H), 6.96 (m, 2H), 6.48 (dd, 1H), 6.41 (dd, 1H), 6.37 (m, 1H), 5.89(tt, 1H), 4.64 (ABq, 2H), 4.34 (m, 1H), 3.87 (dd, 1H), 3.55(dd, 1H),2.41 (bs, 1H). ¹⁹F NMR (CDCl₃) δ−79.3 (d, 3F), −88.6 (m, 2F), −137.2(dt, 2F). HRMS calcd. for C₂₄H₂₁O₃NF₇: 504.1410 [M+H]+, found: 504.1425.

Additional examples of3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols areprepared by one skilled in the art using similar methods, as shown inExample Tables 6 and 7.

Example Table 6. 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H]215 3-OCH₃, 3-CF₃ 462.1115 462.1115 5-CF₃ 216 3-phenoxy 3-SCF₃ 488.1119488.1116 217 3-phenoxy H 388.1524 388.1558 218 3-SO₂-phenyl 3-OCF₂CF₂H552.1080 552.1095

Example Table 7. 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1)-N-R_(SUB2) [M + H] [M +H] 219

322.1419 322.1426

EXAMPLE 220

N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)-benzenemethanamine

EX-220A) To a 1,2-dichloroethane (30 mL) solution of3-(1,1,2,2-tetrafluoroethoxy)-benzaldehyde (2.00 g, 9.0 mmol) was added3-bromoaniline (0.98 mL, 9.0 mmol), NaB(OAc)₃H (2.48 g, 11.7 mmol) andacetic acid (0.57 mL, 10 mmol). The cloudy mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured into water andextracted with dichloromethane. The organic layer was washed withsaturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield 3.27 g(96%) of the desiredN-(3-bromophenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amineproduct as a brown oil which was used without further purification. MSm/z=377[M⁺].

EX-220B) To a dichloromethane (9 mL) solution of the EX-220A amine (3.27g, 8.65 mmol) was added 1,1,1-trifluoro-2,3-epoxypropane (0.968 mL, 11.3mmol) and Yb(OTf)₃ (0.536 g, 0.86 mmol). The cloudy mixture was stirredat room temperature for 24 hours, then diluted with diethyl ether. Theorganic layer was washed with water and brine, dried (MgSO₄) andevaporated to yield 4.20 g (99%) of the desired3-[(3-bromophenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a pale brown oil which can be used without furtherpurification. The formation of the desired product was confirmed by thepresence of the alcohol peak (δ1.5, d) in the ¹H NMR spectrum (C₆D₆). Ananalytical sample was purified by silica gel chromatography eluting with20% ethyl acetate in hexane to give the desired pure product as a yellowoil. FABMS m/z=491 [M+H]⁺. ¹H NMR (CDCl₃) δ3.55-3.63 (m, 1H), 3.88 (dd,1H), 4.36 (m, 1H), 4.69 (s, 2H), 5.914 (tt, 1H), 6.66 (dd, 1H), 6.92 (m,2H), 7.06 (s, 1H), 7.09 (m, 3H), 7.36 (t, 1H).

To a dichloromethane (10 mL) solution of EX-220B aminopropanol (4.20 g,8.57 mmol) was added tert-butyldimethylsilyl trifluoromethanesulfonate(3.0 mL, 13.1 mmol) and triethylamine (2.40 mL, 17.3 mmol). Theresulting solution was stirred at room temperature for 4 hours. Thereaction mixture was diluted with dichloromethane, and washed withsaturated NaHCO₃ and brine.

The organic layer was dried (MgSO₄) and evaporated to an oil.Purification by flash chromatography on silica eluting with 2.5% EtOAcin hexane gave 3.0 g (58%) of the desiredN-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamineproduct as a colorless oil. HRMS calcd for C₂₄H₂₉BrF₇NO₂Si: 606.1098[M+H]⁺, found 606.1118. ¹H NMR (C₆D₆) δ−0.19 (s, 3H), −0.06 (s, 3H),0.88 (s, 9H), 3.38 (m, 2H), 4.11 (s, 2H), 4.12 (q, 1H), 5.10 (tt, 1H),6.33 (dd, 1H), 6.61 (d, 1H), 6.68 (t, 1H), 6.81 (m, 2H), 6.89 (m, 2H),6.97 (t, 1H).

3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

A solution ofN-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroetboxy)benzenemethanamine(75 mg, 0.124 mmol), cesium carbonate (81 mg, 0.248 mmol),4chloro-3-ethylphenol (44 mg, 0.358 mmol), copper triflate benzenecomplex (6.24 mg, 10 mol %), 1-naphthoic acid (43 mg, 0.248 mmol) in 2:1toluene:dimethylacetamide (3.0 mL) was heated at 105° C. for 96 hours.The reaction mixture was filtered through celite, and the solvent wasevaporated. The residue was purified by reverse phase chromatographyeluting with 50-90% acetonitrile in water to afford 16.2 mg (23%) of thedesired3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as an orange oil. HRMS calcd. for C₂₆H₂₃CIF₇NO₃: 566.1332[M+H]⁺, found: 566.1332. ¹H NMR (CDCl₃) δ1.18 (t, 3H), 2.69 (q, 2H),3.50-3.61 (m, 1H), 3.87 (dd, 1H), 4.28-4.39 (m, 1H), 4.63 (s, 2H), 5.88(tt, 1H), 6.32-6.40 (m, 2H), 6.48 (dd, 1H), 6.69 (dd, 1H), 6.87 (d, 1H),7.0-7.34 (m, 5H).

Additional examples of 3-[(3-aryloxyphenyl andheteroaryloxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Tables 8 and 9. Additional examples of3-[(3-arylthiophenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 10.

Example Table 8. 3-[(3-Aryloxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 2222-chloro 538.1019 538.1021 223 2-fluoro 522.1315 522.1310 224 2-fluoro,4-CF₃ 590.1189 590.1155 225 2,3,5-trifluoro 558.1127 558.1109 2263-N,N-dimethylamino 547.1831 547.1844 227 2-fluoro, 3-CF₃ 590.1189590.1184 228 3-NHCOCH₃ 561.1624 561.1590 229 2,3-dichloro 572.0630572.0653 230 2-chloro, 4-fluoro 556.0925 556.0891 231 2-chloro, 4-chloro572.0630 572.0667 232 3-methyl, 5-ethyl 546.1879 546.1899 233 3-ethyl532.1722 532.1706 234 3,5-dimethyl 532.1722 532.1705 235 2,5-difluoro540.1221 540.1255 236 4-(perfluorophenyl)- 741.0796 741.07992,3,5,6-tetrafluoro-phenyl 237 2,3,4-trifluoro 558.1127 558.1161 2382,3-difluoro 540.1221 540.1182 239 3-acetyl 546.1515 546.1549 2403-fluoro 522.1315 522.1337 241 3,5-difluoro 540.1221 540.1217 2424-fluoro, 3-methyl 536.1471 536.1480 243 4-propoxy 562.1828 562.1803 2443-trifluoromethoxy 588.1232 588.1236 245 3-chloro, 4-fluoro 556.0925556.0932 246 4-chloro, 3-fluoro 556.0925 556.0933 247 3,4,5-trimethyl546.1879 546.1901 248 3-trifluoromethyl 572.1283 572.1265 2493-isopropyl 546.1879 546.1878 250 4-isopropyl 546.1879 546.1899 2514-butoxy 576.1958 576.1969 252 3-tert-butyl 560.2035 560.2055 2534-isopropyl, 3-methyl 560.2035 560.2035 254 4-sec-butyl 560.2035560.2051 255 4-(1,1-dimethyl-propyl) 574.2192 574.2208 256 3,4-dichloro572.0630 572.0630 257 4-cyclopentyl 572.2035 572.2029 258 3,4-(CH₂)₄558.1879 558.1881 259 4-benzyl 594.1879 594.1906 260 4-phenyl 580.1722580.1741 261 4-n-butyl 560.2036 560.2033 262 4-ethoxy 548.1672 548.1674263 4-mercapto 536.1130 536.1163 264 3-phenyl 580.1723 580.1772 2654-chloro, 2-fluoro 556.0926 556.0954 266 4-n-propyl 546.1879 546.1878267 4-methylthio 550.1209 550.1251 268 3,5-dimethoxy 564.1623 564.1617269 4-bromo 582.0716 582.0473 270 3-hydoxymethyl 564.1621 564.1617 2713-methyl, 4-methylthio 564.1443 564.1476 272 4-chloro, 3,5-dimethyl552.1176 552.1185 273 4-methoxy 533.1437 533.1458 274 3-methoxy 533.1437533.1450 275 4-chloro 537.0942 537.0944 276 4-(imidazo-1-yl) 569.1549569.1552 277 3,4-dimethyl 531.1644 531.1649 278 3-methyl 517.1488517.1493 279 4-chloro, 3-methyl 551.1098 551.1101 280 4-ethoxy 547.1594547.1594 281 4-methyl 517.1488 517.1495

Example Table 9. 3-[(3-Aryloxy and Heteroaryloxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 2826-methyl-3-pyridyl 518.1440 518.1452 283 2-pyridyl 504.1284 504.1284 2843-isoquinolyl 555.1518 555.1513 285 2-naphthyl 554.1566 554.1578 2863-pyridyl 505.1362 505.1369 287 5-chloro-3-pyridyl 539.0972 539.1002 2885-indolyl 543.1519 543.1630 289 2-methyl-3-pyridyl 519.1518 519.1517

Example Table 10. 3-[(3-Arylthiophenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 290 H519.1518 519.1119 291 4-methoxy 549.1209 549.1216

EXAMPLE 292

3-[[3-[(4-methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

A mixture containingN-(3-bromophenyl)-N-[2[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine(75 mg, 0.124 mmol), cesium carbonate (57.5 mg, 0.176 mmol),4-methoxyaniline (18.6 mg, 0.151 mmol)tris(dibenzylideneacetone)dipalladium(0) (4.6 mg, 0.005 mmol),R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.7 mg, 0.0075 mmol)and toluene (2.5 mL) was heated to 95° C. in a sealed vial for 48 h.Tetrabutylammonium fluoride (1 M, THF, 0.372 mL, 0.372 mmol) was added,and the reaction was stirred at 23° C. for 1.5 h. The reaction mixturewas filtered through celite, and the solvent was evaporated. The residuewas purified by silica gel chromatography eluting with 20% ethyl acetatein hexane to give 49 mg (73%) of the desired3-[[3-[(4-methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as an orange oil. HRMS calcd for C₂₅H₂₃F₇N₂O₃: 532.1597, found:532.1592 [M]⁺. ¹H NMR (CDCl₃) δ3.48-3.57 (m, 1H), 3.77 (s, 3H), 3.83(dd, 1H), 4.33 (m, 1H), 4.59 (s, 2H), 5.87 (tt, 1H), 6.27 (m, 1H), 6.33(bd, 1H), 6.86 (dd, 4H), 7.02-7.12 (m, 4H), 7.31 (t, 1H), 7.41 (m, 1H),7.60 (m, 1H). ¹⁹F NMR (CDCl₃) δ−137.201 (d, 2F), −88.515 (s, 2F),−79.120 (s, 3F).

Additional examples of 3-[[3-(N-arylamino andN-alkyl-N-arylamino)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Tables 11 and 12. Additional examples of3-[[3-(piperidino)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 13.

Example Table 11. 3-[[3-(Arylamino)phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M]⁺ [M]⁺ 293 4-fluoro520.1397 520.1389 294 H 502.1491 502.1473 295 4-trifluoromethyl 570.1365570.1335 296 4-chloro 536.1102 536.1125 297 4-cyano 527.1444 527.1452298 4-CO₂CH₂CH₃ 574.1703 574.1703 299 4-n-propyl 544.1961 544.1959 3004-[[3-(4-methyl-phenyl)]- 660.1971 660.1969 1,2,4-oxadiazol-5-yl] 3014-[COCH(CN)— 641.1761 641.1755 CO₂CH₂CH₃] 302 3-cyano 527.1444 527.1448303 3-CO₂CH₂CH₃ 574.1703 574.1668 304 3-chloro 536.1102 536.1102 3053-methoxy 532.1597 532.1593 306 3,4,5,-trimethoxy 592.1703 592.1703 3073,5-difluoro 538.1303 538.1329 308 4-trifluoromethoxy 586.1314 586.1314309 3,4-dimethoxy 562.1703 562.1713 310 3-trifluoromethyl 570.1365570.1332

Example Table 12. 3-[[3-(N-alkyl-N-Arylamino)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. Rsub₁ Rsub₂ [M]⁺ [M]⁺ 311 H3-trifluoromethyl- 584.1522 584.1518 benzyl 312 —CH₂CH₃ 3-methyl-phenyl544.1961 544.1959 313 n-C₄H₉ 4-CO₂CH₂CH₃- 630.2329 630.2329 phenyl 314—(CH₂)₂CN 4-methyl-phenyl 569.1913 569.1920

Example Table 13. 3-[[3-(N-piperidino)phenyl]-[[3 -(1,1,2,2-tetrafluoro-ethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. Rsub₁ Rsub₂ Mass [M]⁺ Mass [M]⁺ 315 H H494.1804 494.1804 316 H benzyl 584.2274 584.2280 317 —OCH₂CH₂O— 552.1859552.1863

EXAMPLE 318

3-[[3-[(4-methoxyphenyl)methylamino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

To a solution of3-[[3-[(4methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(44.3 mg, 0.083 mmol) in tetrahydrofuran (1.0 mL), methyl iodide (6.21μL, 0.099 mmol) and cesium carbonate (36.6 mg, 0.112 mmol) were added.The dark solution was stirred at 23° C. for 2 h, then heated to 55° C.for 12 h. The reaction mixture was filtered through celite, and theresidue was purified by silica gel chromatography eluting with 20% ethylacetate in hexane to give 25.2 mg (55%) of the desired3-[[3-[(4-methoxyphenyl)methylamino]-phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as an orange oil. HRMS calcd for C₂₆H₂₅F₇N₂O₃: 546.1753, found:546.1750 [M]⁺. ¹H NMR (CDCl₃), δ3.54 (m, 1H), 3.38 (s, 3H), 3.65-3.80(m, 4H), 4.59 (s, 2H), 5.90 (tt, 1H), 6.20 (d, 1H), 6.37 (d, 1H), 6.68(s, 1H), 6.76 (d, 2H), 6.90-7.15 (m, 6H), 7.31 (t, 1H). ¹⁹F NMR (CDCl₃),δ−137.21 (d, 2F), −88.52 (s, 2F), −78.79 (s, 3F).

Additional examples of 3-[[3-[(4-methoxyphenyl)alkylamino andhaloalkylamino)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 14.

Example Table 14. 3-[[3-[(4-methoxyphenyl)alkylamino andhaloalkylamino)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. R_(sub) Mass [M]⁺ Mass [M]⁺ 319 ethyl560.1910 560.1910 320 —(CH₂)₃CF₃ 642.1940 642.1920

EXAMPLE 321

3-[[(5-chloro-2-thienyl)methyl][(3-trifluoromethoxy)phenyl]amino]-1,1,1-trifluoro-2-propanol

EX-321A) 3-Trifluoromethoxyaniline (23.81 g. 134.4 mmol) and3,3,3-trifluoro-1,2-epoxypropane (3.76 g, 33.6 mmol) were placed into asealed tube and heated to 80° C. for 24 h. The excess aniline wasremoved by distillation (70° C. at 16.2 Torr) to give 8.6 g (88%) of thedesired 3-[(3-trifluoromethoxyphenyl)amino]-1,1,1-trifluoro-2-propanolproduct as a light yellow oil. ¹H NMR (CDCl₃) δ3.29-3.37 (m, 1H), 3.55(dd, 1H), 4.20 (m, 1H), 6.48-6.63 (m, 3H), 7.12 (t, 1H). ¹⁹F NMR (CDCl₃)δ−79.36 (s, 3F), −58.44 (s, 3F).

EX-321B) The aminopropanol (18.68 g, 64.6 mmol) from EX-321A andimidazole (10.99 g, 0.162 mmol) were dissolved in dimethylformamide(40.0 mL) and t-butyl-dimethylsilyl chloride (11.69 g, 77.6 mmol) wasadded in 3.0 g portions over 15 min. The reaction was stirred at 23° C.for 18 h. The reaction solution was diluted with ethyl acetate andwashed with water and brine. The organic layer was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by silica gelchromatography eluting with 25% ethyl acetate in hexane to afford 17.08g (66%) of the desired silylatedN-(3-trifluoromethoxyphenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]3,3,3-trifluoro-propylamineproduct as a light golden oil. FABMS m/z=404 [M+H]⁺. ¹H NMR (CDCl₃)δ0.042 (s, 3H), 0.085 (s, 3H), 0.91 (s, 9H), 3.25-3.35 (m, 1H), 3.50(dd, 1H), 4.10 (m, 1 H), 6.40 (bs, 1H), 6.50 (dd, 1H), 6.59 (d, 1H),7.17 (t, 1H).

EX-321C) The silylated aminopropanol (0.157 g, 0.40 mmol) from EX-321Bwas dissolved in tetrahydrofuran (150 μL) and cooled to 0° C. Potassiumtert-butoxide (1.0 M, THF, 0.60 mL, 0.60 mmol) was added in one portionvia syringe. The dark solution was stirred at 0° C. for five minutes.2-Chloro-5-bromomethyl-thiophene (73.5 mg, 0.44 mmol) was added in oneportion to the cooled solution. The reaction mixture was stirred at 0°C. for 15 minutes then warmed to 23° C. for 16 h. Tetrabutyl-ammoniumfluoride (1.0 M, THF, 1.2 mL 1.2 mmol) was added to the dark reactionmixture and stirring followed for 2 h at 23° C. The solution was dilutedwith ethyl acetate and washed with water and brine. The organic layerwas dried (MgSO₄) and concentrated in vacuo. The residue was purified bysilica gel chromatography eluting with 0-20% ethyl acetate in hexane toafford 63.4 mg (39%) of the desired3-[[(5-chloro-2-thienyl)methyl[[(3-trifluoromethoxy)phenyl]amino-1,1,1-trifluoro-2-propanolproduct as a light golden oil. HRMS calcd. for C₁₅H₁₂ClF₆NO₂S: 419.1518,found: 419.1527 [M]⁺. ¹H NMR (CDCl₃) δ3.50-3.56 (m, 1H), 3.77 (dd, 1H),4.28 (m, 1H), 4.67 (s, 2H), 6.62-6.75 (m, 5H), 7.24 (t, 1H). ^(·)F NMR(CDCl₃) δ−79.24 (s, 3F), −58.04 (s, 3F).

Additional examples of 3-[[(aralkyl andheteroaralkyl)][(3-trifluoromethoxy)-phenyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 15.

Example Table 15. 3-[[(aralkyl and heteroaralkyl)][(3-trifluoromethoxy)phenyl]amino]-1,1,1-trifluoro-2-propanols.

Calc. Obs. Ex. Mol. Mass No. R_(SUB) Wt. [M]⁺ 322 3-iodo—benzyl 505 506323 4-difluoromethoxy—benzyl 445 446 324 4-(2-cyanophenyl)—benzyl 480481 325 3-CO₂CH₃—benzyl 437 438 326 2,3,5,6-tetrafluoro-4-methoxy—benzyl481 482 327 3-cyano—benzyl 404 405 328 3,5-difluoro—benzyl 415 416 3292,4-difluoro—benzyl 415 416 330 2,6-difluoro—benzyl 415 416 3314-nitro—benzyl 424 425 332 (1-napthyl)methyl 429 430 333 4-phenyl—benzyl455 456 334 2-chloro-4,5-(OCH₂CH₂O)—benzyl 457 458 335 3-nitro—benzyl424 425 336 4-phenoxy—butyl 437 438 337 3-phenyl—propyl 407 408 3383-(4-methoxy)phenyl—propyl 437 438 339 2-methoxyphenacetyl 437 438 3402-(2,5-dimethoxy-phenyl)-2-oxoethyl 467 468 341 4-CO₂CH₃—benzyl 437 438342 2-(anthraquinonyl)—methyl 509 510 343 perfluorobenzoyl 483 484 3442-(3-indoiyl)ethyl 432 433 345 3-pyridinylmethyl 380 381 346(5-chloro-2-thienyl)—methyl 419 420 347 4-methoxy—benzyl 409 410 3483-methoxy—benzyl 409 410 349 4-pyridinylmethyl 380 381 3503,5-dimethoxy—benzyl 439 440 351 3-(phenyl)propenoyl 419 420 3523-phenyl-2,3-propenyl 405 406 353 3,5-dimethoxy—benzoyl 453 454 3542,4,5-trimethoxy—benzyl 469 470 355 2,5-dimethoxy—benzyl 439 440 3563-CO₂H—benzyl 423 424 357 3-OH—benzyl 395 396 358 2,5-dihydroxy—benzyl411 412 359 3,4,5-trihydroxy—benzyl 427 428 360 3,5-dihydroxy—benzyl 411412 361 2-(phenoxy)phenacetyl 499 500 362 2-quinolinylmethyl 430 431 3632-pyridinylmethyl 380 381 364 2-benzimidazolyl—methyl 419 420 3651-benzyl-2-imidazolyl—methyl 459 460 366(2,6-dichloro-4-pyridinyl)methyl 449 450

EXAMPLE 367

N′-(4-butoxyphenyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-N-[3-(trifluoromethoxy)phenyl]urea

The silylated aminopropanol (0.150 g, 0.372 mmol) from EX-321B wasdissolved in chloroform (0.5 mL). Then 4n-butoxyphenyl isocyanate (78.25mg, 0.409 mmol) was added, and the resulting solution was stirred at 23°C. in a sealed vial for 16 h followed by heating to 65° C. for 24 h. Thereaction was cooled to 23° C., and a solution of tetrabutylammoniumfluoride (1.0 M, THF, 0.5 mL, 0.50 mmol) was added to the reaction,which was then stirred at 23° C. for 2 h. The solution was diluted withethyl acetate and washed with water and brine. The residue was purifiedby silica gel chromatography eluting with 0-50% ethyl acetate in hexaneto afford 73.6 mg (38%) of the desired urea product as a pale yellowglass. FABMS m/z=481 [M+H]⁺. ¹H NMR (CDCl₃), δ0.99 (t, 3H), 1.484 (m,2H), 1.740 (m, 2H), 3.25-3.35 (m, 1H), 3.55 (dd, 1H), 3.94 (m, 21H),4.207 (m, 1H), 6.17 (s, 1H), 6.48 (s, 1H), 6.50-6.65 (m, 2H), 6.83 (d,2H), 7.15 (d, 2H), 7.58 (t, 1H), ¹⁹F NMR (CDCl₃) δ−78.87 (s, 3F), −58.29(s, 3F).

Additional examples of N′-(aryl andsulfonylaryl)-N-(3,3,3-trifluoro-2-hydroxy-propyl)-N-[3-(trifluoromethoxy)phenyl]ureasare prepared by one skilled in the art using similar methods, as shownin Example Table 16.

Example Table 16. N′-(aryl and sulfonylaryl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-N-[3-(trifluorormethoxy)phenyl]ureas.

Ex. Calculated Observed No. R_(SUB) Mol. Wt. Mass [M]⁺ 368 2-CH₃S—phenyl454 455 369 4-biphenyl 484 485 370 4-CH₃-phenyl—SO₂— 486 487

EXAMPLE 371

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenol

EX-371A) To a solution of 3-aminophenol (4.91 g, 45.0 mmol) and3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g, 45.0 mmol) dissolvedin 100 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride(14.28 g 67.5 mmol) and glacial acetic acid (2.7 mL, 47.3 mmol). Thereaction mixture was stirred for 6 h, water was added, and the mixturewas extracted with dichloromethane. The organics were washed withsaturated aqueous sodium bicarbonate then dried over MgSO₄. The driedorganic layer was evaporated to give 11.00 g (78%) of the desired3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol product asa dark orange oil. ¹H NMR (CDCl₃) δ4.32 (s, 2H), 5.88 (tt, 1H), 6.08 (t,1H), 6.17-6.22 (m, 2H), 7.00 (t, 1H), 7.11 (dd, 1H), 7.24-7.27 (m, 2H),7.33 (t, 1H).

A solution of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol (11.0 g,34.9 mmol), 3,3,3-trifluoro-1,2-epoxypropane (4.5 mL, 52.4 mmol) andytterbium trifluoromethanesulfonate (2.2 g, 10 mol %) in 20 mL ofacetonitrile was heated at 50° C. in a sealed glass tube for 16 h. Thereaction mixture was cooled, water was added, and the reaction mixturewas extracted with ether. The ether layer was washed with saturatedaqueous sodium bicarbonate and brine and dried over MgSO₄. The driedorganic layer was evaporated to give 8.07 g (89%) of the desired3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2hydroxypropyl)amino]phenolproduct as a yellow oil. HRMS calcd. for C₁₈H₁₇F₇NO₃: 428.1097 [M+H]⁺,found: 428.1104. ¹H NMR (CDCl₃) δ3.58 (dd, 1H), 3.88 (dd, 1H), 4.39 (m,1H), 4.68 (s, 2H), 5.91 (tt, 1H), 6.25-6.37 (m, 3H), 7.07-7.14 (m, 4H),7.35 (t, 1H).

EXAMPLE 372

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol

To a solution of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenol(100 mg, 0.23 mmol), 3-trifluoromethoxybenzyl bromide (70.0 mg, 0.27mmol) in 2.5 mL of acetone and cesium carbonate (100 mg, 0.31 mmol) wereadded. The reaction mixture was heated to 60° C. for 18 h then cooled.The reaction mixture was filtered through celite, and the solvent wasevaporated. The residue was purified by reverse phase HPLC eluting with50% to 90% acetonitrile in water to afford 63.3 mg (45%) of the desiredbenzyl ether product as an orange oil. HRMS calcd. for C₂₆H₂₂F₁₀NO₄:602.1389 [M+H]⁺, found: 602.1380. ¹H NMR (CDCl₃) δ3.61 (dd, 1H), 3.83(dd, 1H), 4.32-4.39 (m, 1H), 4.62 (s, 2H), 4.98 (s, 2H), 5.84 (tt, 1H),6.43-6.55 (m, 3H), 7.04-7.42 (m, 9H).

Additional examples of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[(substituted)methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods as shown inExample Tables 17 and 18.

Example Table 17. 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[(substituted-phenyl)methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 373 H518.1566 518.1578 374 4-trifluoromethoxy 602.1389 602.1383 375 4-nitro563.1417 563.1457 376 2,3,4,5,6-pentafluoro 608.1095 608.1092 3773,5-di(trifluoromethyl) 654.1314 654.1308 378 3,5-difluoro 554.1378554.1390 379 3-trifluoromethyl 586.1440 586.1419 3802,3,5,6-tetrafluoro-4-trifluoro- 658.1063 658.1003 methyl 3814-fluoro-2-trifluoromethyl 604.1346 604.1321 382 3-nitro 563.1417563.1416 383 3-cyano 543.1519 543.1523 384 4-cyano 543.1519 543.1517 3854-methyl 532.1723 532.1729 386 2,3,5,6-tetrafluoro-4-methoxy 620.1295620.1261 387 3-methoxycarbonyl 576.1621 576.1613 388 4-methoxycarbonyl576.1621 576.1614 389 4-difluoromethoxy 584.1483 584.1480 390 2-fluoro536.1472 536.1465 391 4-fluoro 536.1472 536.1454 392 2,4,6-trifluoro572.1284 572.1267 393 3-chloro-2-fluoro 570.1082 570.1069 3942-6-difluoro 554.1378 554.1385 395 2,4-difluoro 554.1378 554.1346 3962,4-di(trifluoromethyl) 654.1314 654.1321 397 2,5-difluoro 554.1378554.1350 398 3,4-difluoro 554.1378 554.1381 399 2,3-difluoro 554.1378554.1364 400 2-fluoro-3-trifluoromethyl 604.1346 604.1329 401 3-bromo596.0671 596.0641 402 3-methyl 532.1723 532.1692 403 2-bromo 596.0671596.0666 404 2-chloro 552.1176 552.1175 405 3-iodo 644.0533 644.0517 4063-fluoro 536.1472 536.1475 407 3-methoxy 548.1672 548.1676 4082,3,5-trifluoro 572.1284 572.1276 409 4-trifluoromethylthio 618.1161618.1165 410 3-trifluoromethylthio 618.1161 618.1151 4113-fluoro-5-trifluoromethyl 604.1346 604.1309 4124-fluoro-3-trifluoromethyl 604.1346 604.1336 413 4-(phenylmethoxy)624.1985 624.1956 414 4-phenyl 594.1879 594.1845 415 4-ethyl 546.1879546.1862 416 4-trifluoromethyl 586.1440 586.1400 417 2-methyl-3-nitro577.1573 577.1576 418 4-tert—butyl 574.2192 574.2163 419 3,4-dimethyl546.1879 546.1881 420 3-chloro 552.1176 552.1157 421 4-bromo 596.0671596.0669 422 3,5-dichloro 586.1787 586.1378 423 3,5-dimethyl 546.1879546.1890 424 4-chloro 552.1176 552.1188 425 2-fluoro-3-methyl 550.1628550.1625 426 3-phenoxy 610.1828 610.1819 427 4-isopropyl 560.2036560.2020

Example Table 18. 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-[3-[(substituted)-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 4283-pyridylmethyl 519.1519 519.1483 429 1-phenylethyl 532.1723 532.1711430 1-benzylimidazol-2-ylmethyl 598.1941 598.1946 4315-chlorobenzo[b]thien-3-ylmethyl 608.0897 608.0884 432 2-pyridylmethyl519.1519 519.1522 433 4-pyridylmethyl 519.1519 519.1515

EXAMPLE 434

3-[[3-[(4-aminophenyl)methoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-434A) A solution of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-nitro-phenyl)methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol(42.0 mg, 0.07 mmol) and zinc dust (37 mg, 0.57 mmol) in acetic acid(0.5 mL) was stirred for 4 d. The reaction mixture was filtered, and thesolvent was evaporated. The residue was purified by reverse phase HPLCeluting with 50% to 90% acetonitrile in water to afford 15.4 mg (39%) ofthe desired reduced amine product as a brown oil. HRMS calcd. forC₂₅H₂₄F₇N₂O₃: 533.1675 [M+H]⁺, found: 533.1656. ¹H NMR (acetone-d₆) 3.60(dd, 1R), 3.85 (m, 1H), 3.90 (s, 2H), 4.45 (m, 1H), 4.73 (s, 2H),6.22-6.64 (m, 4H), 6.94 (dd, 1H), 7.12-7.45 (m, 9H).

EX-434B)3-[[3-[(3-aminophenyl)methoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolis prepared by one skilled in the art using similar methods. HRMS calcd.for C₂₅H₂₄F₇N₂O₃: 533.1675 [M+H]⁺, found: 533.1654.

EXAMPLE 435

3-[[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]methyl]benzoicAcid

EX-435A) A solution of ethyl3-[[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]methyl]benzoate (22.1 mg, 0.04 mmol) and lithiumhydroxide (5 mg, 0.12 mmol) in water (1 mL) and tetrahydrofuran (0.5 mL)was heated at 80° C. for 16 h. The reaction mixture was added to 6 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate, and the solvent was evaporated. Theresidue was purified by reverse phase HPLC eluting with 10% to 90%acetonitrile in water to afford 5.6 mg (19%) of the desired benzoic acidproduct as a brown oil. HRMS calcd. for C₂₆H₂₃F₇NO₅: 562.1464 [M+H]⁺,found: 562.1418. ¹H NMR (acetone-d₆) δ3.64 (dd, 1H), 3.95 (m, 1H),4.45-4.50 (m, 1H), 4.80 (s, 2H), 5.12 (s, 2H), 6.27-6.63 (m, 4H),7.06-7.27 (m, 4H), 7.41 (t, 1H), 7.50 (t, 1H), 7.66 (d, 1H), 7.99 (d,1H), 8.10 (s, 1H).

EX-435B)4-[[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]methyl]benzoicacid is prepared by one skilled in the art using similar methods. HRMScalcd. for C₂₆H₂₃F₇NO₅: 562.1464 [M+H]⁺, found: 562.1445.

EXAMPLE 436

3-[[3-(2-nitrophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

A solution of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenol(100 mg, 0.23 mmol), 1-bromo-2-nitrobenzene (52.4 mg, 0.26 mmol),copper(I) trifluoromethanesulfonate benzene complex (3 mg, 2.5 mol %)and cesium carbonate (100 mg, 0.31 mmol) in toluene (1 mL) and ethylacetate (1 mL) was heated at 95° C. in a sealed vial for 4 d. Thereaction mixture was filtered through celite, and the solvent wasevaporated. The residue was purified by reverse phase HPLC eluting with50% to 90% acetonitrile in water to afford 14.1 mg (11%) of the desired2-nitrophenyl ether product as an orange oil. HRMS calcd. forC₂₄H₂₀F₇N₂O₅: 549.1260 [M+H]⁺, found: 549.1235. ¹H NMR (CDCl₃) δ3.63(dd, 1H), 3.84 (dd, 1H), 4.35-4.42 (m, 1H), 4.64 (s, 2H), 5.90 (tt, 1H),6.47-6.67 (m, 3H), 6.98-7.50 (m, 8H), 7.97 (d, 1H).

Additional examples of3-[[3-aryloxyphenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example 19.

Example Table 19. 3-[[3-aryloxyphenyl][3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1 -trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 4374-tert—butylphenyl 560.2036 560.2050 438 4-nitrophenyl 549.1260 549.1306439 4-bromo-2-nitrophenyl 627.0366 627.0375 440 3-fluoro-2-nitrophenyl567.1166 567.1135 441 2-cyano-3-pyridyl 530.1315 530.1300 4425-carboxy-3-pyridyl 549.1260 549.1269 443 4-fluoro-2-pyridyl 523.1268523.1243 444 3-trifluoromethyl-2-pyridyl 573.1236 573.1205 4455-trifluoromethyl-2-pyridyl 573.1236 573.1197 446 5-bromo-2-pyridyl583.0667 583.0405 447 2-methyl-5-nitrophenyl 563.1417 563.1416 448thiazol-2-yl 511.0926 511.0911 449 5-pyrimidinyl 506.1315 506.1315

EXAMPLE 450

3-[[3-(4-aminophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanoland3-[[3-[4-(ethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

A solution of3-[[3-(4-nitrophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol(33.8 mg, 0.06 mmol) in ethanol and 5% palladium on carbon (4 mL) wasplaced under 40 psi hydrogen gas for 7 h. The mixture was filteredthrough celite, the solvent was evaporated, and the residue was purifiedby silica gel chromatography eluting with 25% ethyl acetate in hexane togive 13.4 mg (42%) of (EX-450A) as3-[[3-(4-aminophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanoland 13.9 mg (41%) of (EX-450B) as3-[[3-[4-(ethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolboth as orange oils.3-[[3-(4-aminophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol:HRMS calcd. for C₂₄H₂₂F₇N₂O₃: 519.1519 [M+H]⁺, found: 519.1529. ¹H NMR(acetone-d₆) δ3.63 (dd, 1H), 3.96 (dd, 1H), 4.42-4.58 (m, 1H), 4.80 (s,2H), 5.88 (m, 1H), 6.20 (m, 1H), 6.32-6.77 (m, 6H), 6.92 (d, 1H),7.06-7.26 (m, 3H), 7.43 (m, 1H).3-[[3-[4-(ethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol:HRMS calcd. for C₂₆H₂₆F₇N₂O₃: 547.1832 [M+H]⁺, found: 547.1819. ¹H NMR(acetone-d₆) δ1.23 (t, 3H), 3.17 (q, 2H), 3.63 (dd, 1H), 3.96 (dd, 1H),4.42-4.58 (m, 1H), 4.79 (s, 2H), 5.85 (d, 1H), 6.20 (m, 1H), 6.33 (m,1H), 6.47 (m, 1H), 6.50 (tt, 1J), 6.61 (d, 2H), 6.78 (d, 2H), 7.09 (t,1H), 7.20 (m, 1H), 7.23 (d, 1H), 7.42 (m, 1H).

EXAMPLE 451

3-[[3-(2-pyridinyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

A solution of3-[(3-bromophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(100 mg, 0.22 mmol), 2-tributylstannyl pyridine (96 mg, 0.26 mmol),dichlorobis(triphenylphospine)palladium(II) (6 mg, 6.7 mol %) andlithium chloride (46 mg, 1.09 mmol) in toluene (4 mL) was heated at 105°C. for 16 h. The reaction mixture was filtered through celite, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography eluting with 25% ethyl acetate in hexane to afford 47.7mg (45%) of the desired pyridyl product as an orange oil. HRMS calcd.for C₂₃H₂₀F₇N₂O₂: 489.1377 [M+H]⁺, found: 489.1413. ¹H NMR (acetone-d₆)δ3.78 (dd, 1H), 4.06 (dd, 1H), 4.52-4.61 (m, 1H), 4.94 (s, 2H), 5.89 (d,1H), 6.43 (tt, 1H), 6.94 (m, 1H), 7.18 (m, 1H), 7.22-7.42 (m, 5H), 7.60(s, 1H), 7.80 (m, 2H), 8.61 (m, 1H).

Additional examples of3-[[3-(heteroaryl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 20.

Example Table 20. 3-[[3-(heteroaryl)phenyl][[3-(1,1,2,2-tetra-fluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 4522-thienyl 494.1024 494.0987 453 2-furyl 478.1025 478.1025 454 3-pyridyl489.1413 489.1391 455 3-methyl-2-pyridyl 503.1570 503.1531

EXAMPLE 456

1-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)benzoyl]piperidine

EX-456A) Ethyl 3-aminobenzoate (6.75 mL, 0.045 mol) and3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (10 g, 45 mmol) weredissolved in 100 mL of dichloroethane and acetic acid (2.7 mL, 47 mmol),then solid NaBH(OAc)₃ (14.3 g, 67 mmol) was added. The mixture wasstirred at room temperature for 3 hours, then quenched with aqueoussodium bicarbonate and extracted with dichloromethane. The organic layerwas washed with brine, then dried over MgSO₄, and evaporated to give16.7 g (98%) of the desired ethyl3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzoate productas a yellow oil. ¹H NMR (CDCl₃) δ1.3 (t, 3H), 4.3 (q, 2H), 4.5 (s, 2H),6.5 (tt, 1H), 6.9 (d, 1H), 7.1-7.4 (m, 7H).

EX-456B) A solution of EX-456A (16.7 g, 45 mmol) and1,1,1-trifluoro-2,3-epoxypropane (4.26 mL, 49.5 mmol) were dissolved in30 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (2.79g, 4.5 mmol) was added, and the stirred solution was warmed to 50° C.for 18 hours. The reaction was quenched with water and extracted withether. The ether layer was washed with brine, then dried over MgSO₄. Thecrude product was purified by flash column chromatography on silica geleluting with dichloromethane to give 12 g (55%) of the desired ethyl3-[[[3-(1,1,2,2-tetra-fluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]-benzoateproduct as a colorless oil, which was greater than 98% pure by reversephase HPLC analysis. HRMS calcd. for C₂₁H₂₁F₇NO₄: 484.1359 [M+H]⁺,found: 484.1342. ¹H NMR (CDCl₃) δ1.4 (t, 3H), 3.6 (dd, 1H), 3.9 (dd,1H), 4.3 (m, 3H), 4.7 (dd, 2H), 5.9 (tt, 1H), 6.9 (d, 1H), 7.1-7.2 (m,3H), 7.2-7.4 (m, 2H), 7.5 (m, 1H).

To a solution of piperidine (102 μL, 1.03 mmol) in toluene (620 μL) wasadded 2 M trimethylaluminum in toluene (620 μL), and the solution wasstirred for 2 h.

To the reaction mixture was added a solution of ethyl3-[(1,1,1-trifluoro-2-hydroxypropyl)][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzoate(100 mg, 0.21 mmol) in toluene (1 mL). The reaction mixture was heatedat 40° C. for 20 h and 60° C. for 5 h, then cooled. To the reactionmixture was added water dropwise followed by 2 M hydrochloric acid andethyl acetate. The solution was placed on a celite plug for 5 min, theneluted with dichloromethane, and the solvent was evaporated. The residuewas purified by reverse phase HPLC eluting with 50% to 90% acetonitrilein water to afford 42.6 mg (38%) of the desired1-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]-(3,3,3-trifluoro-2-hydroxypropyl)benzoyl]piperidineproduct as an orange oil. HRMS calcd. for C₂₄H₂₆F₇N₂O₃: 523.1832 [M+H]⁺,found: 523.1815. ¹H NMR (acetone-d₆) δ1.22-1.63 (m, 6H), 3.16-3.62 (m,4H), 3.74 (dd, 1H), 4.00 (dd, 1H), 4.44-4.55 (m, 1H), 4.83 (s, 2H), 6.46(tt, 1H), 6.64-6.69 (m, 2H), 6.83 (dd, 1H), 7.14-7.28 (m, 4H), 7.41 (t,1H).

Additional examples ofN,N-disubstituted-3-[(3,3,3-trifluoro-2-hydroxypropyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzamideare prepared by one skilled in the art using similar methods, as shownin Example Table 21.

Example Table 21. N,N-disubstituted-3-[(3,3,3-trifluoro-2-hydroxy-propyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzamide

Calculated Observed Ex. Mass Mass No. R_(SUB) R′_(SUB) [M + H]⁺ [M + H]⁺457 H isopropyl 497.1675 497.1697 458 H n-butyl 511.1832 511.1809 459 Hcyclohexyl 537.1988 537.1969 460 H tert—butyl 511.1832 511.1845 461 Hcyclopentyl 523.1832 523.1854 462 H neo-pentyl 525.1988 525.2028 463 H2,2,2-trifluoroethyl 537.1236 537.1250 464 H 2,2,3,3,4,4,4-hepta-637.1172 637.1177 fluorobutyl 465 H phenylmethyl 545.1675 545.1705 466 H(3-trifluoromethoxy)- 629.1498 629.1510 phenylmethyl 467 H4-(fluorophenyl)methyl 563.1581 563.1611 468 methyl phenyl 545.1675545.1631 469 methyl phenylmethyl 559.1832 559.1853 470—CH₂CH₂N(CH₃)CH₂CH₂— 538.1941 538.1969 471 —CH₂CH₂OCH₂CH₂— 525.1624525.1615 472 —CH₂CH₂CH₂CH₂— 509.1675 509.1675

EXAMPLE 473

3-[[3-[(1-ethylethyl)thio]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

EX-473A) 3-Aminobenzenethiol (2.4 mL, 22.5 mmol) and3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (5 g, 22.5 mmol) weredissolved in 40 mL of dichloroethane and acetic acid (1.35 mL, 23.7mmol), then solid NaBH(OAc)₃ (6.2 g, 29.3 mmol) was added. The mixturewas stirred at room temperature for 18 hours, then quenched with waterand diluted with dichloromethane. The organic layer was washed withaqueous saturated sodium bicarbonate, then dried over MgSO₄, andconcentrated in vacuo. The crude product was purified by flash columnchromatography on silica gel eluting with ethyl acetate:hexane 1:10 togive 5.36 g (72%) of the desired3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzenethiolproduct as a brown oil. ¹H NMR (CDCl₃) δ3.4 (s, 1H), 4.4 (s, 2H), 5.9(tt, 1H), 6.4 (dd, 1H), 6.55 (m, 1H), 6.65 (d, 1H), 7.05 (t, 1H),7.2-7.4 (m, 4H).

EX-473B) The EX-473A benzenethiol amine (5.36 g, 16.2 mmol) and1,1,1-trifluoro-2,3-epoxypropane (1 g, 1.6 mmol) were dissolved in 20 mLof acetonitrile. Ytterbium (III) trifluoromethanesulfonate (1 g, 1.6mmol) was added, and the stirred solution was warmed to 50° C. for 48hours, at which time HPLC analysis indicated that no secondary aminestarting material remained. The reaction was quenched with water andextracted with ether. The ether layer was washed with brine, then driedover MgSO₄, and concentrated in vacuo. The crude product was purified byflash column chromatography on silica gel eluting with ethylacetate:hexane 1:10 to give 4.5 g (63%) of the desired3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzenethiolproduct as a yellow oil. ¹H NMR (CDCl₃) δ3.0 (s, 1H), 3.6 (dd, 1H), 3.9(dd, 1H), 4.2 (m, 1H), 4.7 (m, 2H), 5.9 (tt, 1H), 6.5 (dd, 1H), 6.7 (m,2H), 7.1 (m, 4H), 7.4 (t, 1H). HRMS calcd. for C₃₆H₃₁F₁₄N₂O₄S₂: 885.1502[2(M−1)+H]⁺, found: 885.1471.

The EX-473B thiol product (150 mg, 0.34 mmol) and 2-iodopropane (37 μL,0.37 mmol) were dissolved in 2 mL of acetonitrile. Cesium carbonate (144mg, 0.44 mmol) was added, and the stirred solution was warmed to 55° C.for 18 hours, at which time HPLC analysis indicated that nothiol/disulfide starting material remained. The reaction was quenchedwith water and filtered through pre-wetted celite eluting with ethylacetate. The solvent was evaporated, and the residue was purified byreverse phase HPLC eluting with 10% to 90% acetonitrile in water toafford 69 mg (42%) of the desired3-[[3-[(1-methylethyl)thio]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a yellow oil, which was greater than 98% pure by reversephase HPLC analysis. HRMS calcd. for C₂₁H₂₃F₇NO₂S: 486.1338 [M+H]⁺,found: 486.1351. ¹H NMR (CDCl₃) δ1.2 (t, 3H), 3.3 (q, 1H), 3.6 (dd, 1H),3.9 (dd, 1H), 4.3 (m, 1H), 4.7 (m, 3H), 5.9 (tt, 1H), 6.7 (dd, 1H), 6.9(m, 2H), 7.0-7.2 (m, 4H), 7.3 (t, 1H).

Additional examples of 3-[[3-(alkanoyl-, aryl-, heteroaryl-, andaralkylthio)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 22.

Example Table 22. 3-[[3-alkanoyl-, aryl-, heteroaryl-, and aralkylthio)-phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 4744-pyridyl 521.1134 521.1115 475 4-nitrophenyl 565.1032 565.1034 4764-piperidyl 527.1603 527.1597 477 2-pyridylmethyl 535.1290 535.1291 4784-acetylphenyl 562.1287 562.1261 479 4-(methylsulfonyl)phenyl 598.0957598.0946 480 (4-chloro-thien-2-yl)methyl 574.0512 574.0523 481 acetyl486.0974 486.0936

EXAMPLE 482

3-[[3-[(1-methylethyl)sulfonyl]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

To a solution of3-[[3-(1-methylethyl)thio]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(58 mg, 0.12 mmol) in 2 mL of trifluoroacetic acid, was added 30%aqueous H₂O₂ (28 μL, 0.25 mmol). The mixture was stirred at roomtemperature for 18 hours, then quenched with 5% aqueous sodium hydroxideand extracted with ether. The organic layer was concentrated in vacuo.The crude product was purified by reverse phase HPLC eluting with 10% to90% acetonitrile in water to give 29.5 mg (48%) of the desired sulfoneproduct as a brown oil, which was greater than 98% pure by reverse phaseHPLC analysis. HRMS calcd. for C₂₁H₂₃F₇NO₄S: 518.1236 [M+H]⁺, found:518.1226. ¹H NMR (CDCl₃) δ1.1 (d, 6H), 3 (q, 1H), 3.7 (dd, 1H), 3.9 (dd,1H), 4.3 (m, 1H), 4.7 (s, 1H), 5.9 (tt, 1H), 7 (m, 2H), 7.1-7.2 (m, 4H),7.3 (m, 2H).

Additional examples of 3-[(3-(aryl-, heteroaralkyl-, andheterocyclylsulfonyl)phenyl][[3-(1,1,2,2-tetra-fluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 23.

Example Table 23. 3-[(3-(aryl-, heteroaralkyl-, and heterocyclyl-sulfonyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 4834-nitrophenyl 597.0930 597.0925 484 4-piperidyl 559.1502 559.1526 4853-(pyridyl-N-oxide)methyl 583.1138 583.1137 486 4-acetylphenyl 594.1185594.1181 487 4-(methylsulfonyl)phenyl 630.0855 630.0826

EXAMPLE 488

3-[[3-(cyclohexylmethoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](1,1,1-trifluoro-2-hydroxyproxyl)-amino]phenol(100 mg, 0.23 mmol) and bromomethylcyclohexane (42 μL, 0.30 mmol) weredissolved in 2 mL of acetonitrile. Cesium carbonate (144 mg, 0.44 mmol)was added, and the stirred solution was warmed to 50° C. for 48 hours,at which time HPLC analysis indicated that no phenolic starting materialremained. The reaction was quenched with water and filtered throughpre-wetted celite eluting with ethyl acetate. The solvent was evaporatedand the residue was purified by reverse phase HPLC eluting with 10% to90% acetonitrile in water to afford 55 mg (35%) of the desired etherproduct as a brown oil, which was greater than 99% pure by reverse phaseHPLC analysis. HRMS calcd. for C₂₅H₂₉F₇NO₃: 524.2036 [M+H]⁺, found:524.2028. ¹H NMR (CDCl₃) δ0.9-1.4 (m, 5H), 1.7-1.9 (m, 6H), 3.6 (m, 3H),3.9 (dd, 1H), 4.3 (m, 1H), 4.7 (m, 2H), 5.1 (s, 1H), 5.9 (tt, 1H), 6.5(m, 3H), 7.0-7.4 (m, 5H).

Additional examples of 3-[(3-alkoxy-andcycloalkoxy-phenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 24.

Example Table 24. 3-[(3-alkoxy- and cycloalkoxy-phenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 489isopropyl 470.1488 470.1565 490 (methoxycarbonyl)methyl 500.1308500.1297 491 cyanomethyl 467.1206 467.1228 492 2-methylpropyl 484.1723484.1718 493 2-oxobutyl 498.1515 498.1529 494 cyclohexyl 510.1880510.1910 495 5-oxohexyl 526.1828 526.1827 496 4-(methoxycarbonyl)butyl542.1777 542.1827 497 2-(phenylsulphonyl)ethyl 596.1342 596.1349 4982-pyrrolidinylethyl 525.1988 525.2008 499 3-(methoxycarbonyl)-2-propenyl526.1464 526.1482 500 carbamoylmethyl 485.1311 485.1304 5013-cyanopropyl 495.1519 495.1541 502 1-(N-phenylcarbamoyl)ethyl 575.1780575.1778 503 2-oxo-2-phenylethyl 546.1515 546.1543 504 3-hydroxypropyl486.1515 484.1481 505 2-methoxyethyl 486.1515 486.1537 506 neo-pentyl498.1879 498.1845 507 4-tetrahydropyranyl 512.1672 512.1631 5081-ethoxycarbonylbutyl 556.1934 556.1948 509 cyclopentyl 496.1723496.1719 510 3-methyl-2-butenyl 496.1722 496.1675 5112-(N,N-dimethylamino)ethyl 499.1831 499.1826 5123-hydroxy-2,2-dimethylpropyl 514.1828 514.1814 5133,3-dimethyl-2-oxobutyl 526.1828 526.1806

EXAMPLE 514

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[(3-trifluoromethyl)-phenyl]methyl]phenyl]amino]-1,1,1-trifluoro-2-propanol

EX-514A) To a solution of (3-nitrobenzene)methanol (10 g, 65.3 mmol) in50 mL of 5% aqueous sodium hydroxide, was added dimethylsulfate (20 g,156 mmol). The mixture was stirred at 70° C. for 18 hours, then dilutedwith water and ethyl acetate. The organic layer was washed with water,then dried over MgSO₄, and concentrated in vacuo. The crude product waspurified by flash column chromatography on silica gel eluting with ethylacetate:hexane 1:5 to give 4.73 g (43%) of the desired3-(methoxy-methyl)nitrobenzene product as a yellow oil. ¹H NMR (CDCl₃)δ3.5 (s, 3H), 4.5 (s, 2H), 6.5 (t, 1H), 7.7 (d, 1H), 8.1 (d, 1H), 8.2(s, 1H).

EX-514B) The 3-(methoxymethyl)nitrobenzene (4.18 g, 25 mmol) fromEX-514A was dissolved in 160 mL of acetic acid. Zinc dust (5 g, 76.5mmol) was added, and the solution was stirred at room temperature for 18hours, at which time HPLC analysis indicated that no3-(methoxymethyl)nitrobenzene starting material remained. The reactionmixture was filtered through celite and concentrated in vacuo. Theresidue was dissolved in ethyl acetate and washed with aqueous saturatedsodium bicarbonate. The organic layer was washed with water, then driedover MgSO₄, and concentrated in vacuo to give 3.4 g (99%) of the desired3-(methoxymethyl)aniline as a brown oil. The crude product was usedwithout further purification. HRMS calcd. for C₈H₁₂NO: 138.0919 [M+H]⁺,found: 138.0929. ¹H NMR (CDCl₃) δ3.4 (s, 3H), 3.7 (s, 2H), 4.4 (s, 2H),6.6 (d, 1H), 6.7 (m, 2H), 7.2 (t, 1H).

EX-514C) The 3-(methoxymethyl)aniline (1.85 g, 13.51 mmol) product fromEX-514B and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (3 g, 13.5 mmol)were dissolved in 25 mL of dichloroethane and acetic acid (0.85 mL, 14.8mmol), then solid NaBH(OAc)₃ (3.73 g, 17.6 mmol) was added. The mixturewas stirred at room temperature for 48 hours, then quenched with aqueoussaturated sodium bicarbonate and diluted with ethyl acetate. The organiclayer was washed with brine. then dried over MgSO₄, and concentrated invacuo to give 4.27 g (12.4 mmol) of crude product. The crude product and1,1,1-trifluoro-2,3-epoxypropane (1.2 mL. 13.7 mmol) were dissolved in20 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.77g, 1.24 mmol) was added, and the stirred solution was warmed to 50° C.for 18 hours. The reaction was quenched with water and extracted withethyl acetate. The organic layer was washed with brine, then dried overMgSO₄, and concentrated in vacuo to give 5.96 g (97%) of the desired3-[[3-(methoxymethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a brown oil. The crude product was greater than 95% pure byreverse phase HPLC analysis and was used without further purification.HRMS calcd. for C₂₀H₂₁F₇NO₃: 456.1410 [M+H]⁺. found: 456.1409. ¹H NMR(CDCl₃) δ3.3 (s, 3H), 3.6 (dd, 1H), 3.9 (dd, 1H), 4.3 (m, 1H), 4.4 (s,2H), 4.7 (m, 2H), 5.9 (tt, 1H), 6.6-6.8 (m, 3H), 7.1-7.2 (m, 4H), 7.3(t, 1H).

EX-514D) The3-[[3-(methoxymethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]aminol-]1,1,1-trifluoro-2-propanolfrom EX-514C (1 g, 2.2 mmol) was dissolved in 10 mL of dichloromethane.The solution was cooled to −50° C. and a 1 M solution of BBr₃ indichloromethane (2.3 mL, 2.3 mmol) was added. The solution was stirredat −50° C. for 1 hour and warmed to room temperature over 1 hour, atwhich time HPLC analysis indicated that no methyl ether startingmaterial remained. The reaction mixture was quenched with aqueoussaturated sodium bicarbonate and diluted in dichloromethane. The organiclayer was washed with brine, then dried over MgSO₄, and concentrated invacuo. The crude product was purified by flash column chromatography onsilica gel eluting with ethyl acetate:hexane 1:7 to give 0.65 g (59%) ofthe desired3-[[3-(bromomethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a brown oil. HRMS calcd. for C₁₉H₁₈BrF₇NO₂: 504.0409 [M+H]⁺,found: 504.0361. ¹H NMR (CDCl₃) δ3.3 (s, 1H), 3.6 (dd, 1H), 3.9 (dd,1H), 4.3 (m, 1H), 4.4 (s, 2H), 4.8 (m, 2 H), 5.9 (tt, 1H), 6.7 (d, 1H),6.8-6.9 (m, 2H), 7.1-7.3 (m, 4H), 7.4 (t, 1H).

The3-[[3-(bromomethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolfrom EX-514D (0.1 g, 0.19 mmol) and 3-trifluoromethyl-benzeneboronicacid (47.5 mg, 0.25 mmol) were dissolved in 2 mL of toluene and 0.2 mLof 2 M aqueous sodium carbonate. Pd(PPh₃)₄ was added, and the solutionwas stirred at 105° C. for 2.5 hours, at which time HPLC analysisindicated that no bromomethyl starting material remained. The reactionmixture was filtered through celite and concentrated in vacuo. Theresidue was quenched with water and filtered through pre-wetted celiteeluting with ethyl acetate. The solvent was evaporated, and the residuewas purified by reverse phase HPLC eluting with 10% to 90% acetonitrilein water to afford 16.7 mg (15%) of the desired3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-[3-[(3-trifluoromethyl)phenyl]methyl]phenyl]-amino]-1,1,1-trifluoro-2-propanolproduct as a brown oil. HRMS calcd. for C₂₆H₂₂F₁₀NO₂: 570.1413 [M+H]⁺,found: 570.1480. ¹H NMR (CDCl₃) δ3.8 (m, 2H), 4.0 (s, 2H), 4.3 (m, 1H),4.5 (d, 1H), 4.8 (d, 1H), 5.9 (tt, 1H), 6.6-6.8 (m, 4H), 6.9-7.1 (m,31H), 7.2-7.5 (m, 5H).

Additional examples of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(aryl)methyl]phenylamino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 25.

Example Table 25. 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-[3-(aryl)methyl]phenylamino]-1,1,1-trifluoro-2-propanols.

Example Calculated Observed Mass Number R_(SUB) Mass [M + H]⁺ [M + H]⁺515 H 502.1617 502.1609 516 3-nitro 547.1468 547.1449 517 4-methyl516.1774 516.1769 518 3,5-dichloro 570.0838 570.0801 519 4-fluoro520.1523 520.1505 520 4-tert-butyl 558.2243 558.2236 5213-methyl-4-fluoro 534.1679 534.1688 522 3-methyl-4-chloro 550.1384550.1380 523 3,4-dimethyl 530.1930 530.1887 524 3-chloro, 4-fluoro554.1133 554.1108 525 3-chloro 536.1227 536.1218 526 4-methylthio548.1494 548.1503 527 3-methoxy 532.1723 532.1705

EXAMPLE 528

4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]benzenesulfonamide

EX-528A) 3-nitroaniline (1.87 g, 13.51 mmol) and3-(1,1,2,2-tetrafluoroethoxy)-benzaldehyde (3 g, 13.5 mmol) weredissolved in 25 mL of dichloroethane and acetic acid (0.85 mL, 14.9mmol), then solid NaBH(OAc)₃ (3.73 g 17.6 mmol) was added. The mixturewas stirred at room temperature for 48 hours, then quenched with aqueoussaturated sodium bicarbonate and diluted with ethyl acetate. The organiclayer was dried over MgSO₄, and concentrated in vacuo. The crude productwas purified by flash column chromatography on silica gel eluting withethyl acetate:hexane 1:7 to give 3.25 g (70%) of the desiredN-(3-nitrophenyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethan-amineproduct as a brown oil. HRMS calcd. for C₁₅H₁₃F₄N₂O₃: 345.0862 [M+H]⁺,found: 345.0864. ¹H NMR (CDCl₃) δ4.4 (s, 2H), 4.5 (s, 1H), 5.9 (tt, 1H),6.9 (d, 1H), 7.1 (d, 1H), 7.2-7.3 (m, 3H), 7.4 (m, 2H), 7.5 (d, 1H).

EX-528B)N-(3-nitrophenyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine (3.25g, 9.44 mmol) from EX-528A and 1,1,1-trifluoro-2,3-epoxypropane (0.895mL, 10.4 mmol) were dissolved in 15 mL of acetonitrile. Ytterbium (III)trifluoromethane-sulfonate (0.77 g, 1.24 mmol) was added, and thestirred solution was warmed to 55° C. for 48 hours. The reaction wasquenched with water and extracted with ethyl acetate. The organic layerwas dried over MgSO₄, and concentrated in vacuo. The crude product waspurified by flash column chromatography on silica gel eluting with ethylacetate:hexane 1:10 to give 1.93 g (45%) of the desired3-[(3-nitrophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a brown oil. HRMS calcd. for C₁₈H₁₆F₇N₂O₄: 457.0998 [M+H]⁺,found: 457.1008. ¹H NMR (CDCl₃) δ3.7 (dd, 1H), 3.9 (dd, 1H), 4.4 (m,1H), 4.8 (m, 2H), 5.9 (tt, 1H), 7.0-7.2 (m, 4H), 7.3-7.4 (m, 2H), 7.6(m, 2H).

EX-528C) The3-[(3-nitrophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(1.93 g, 4.2 mmol) from EX-528B) was dissolved in 60 mL of acetic acid.Zinc dust (2.1 g, 31.5 mmol) was added, and the solution was stirred atroom temperature for 18 hours, at which time HPLC analysis indicatedthat no nitro starting material remained. The reaction mixture wasfiltered through celite and concentrated in vacuo. The residue wasdissolved in ethyl acetate and washed with aqueous saturated sodiumbicarbonate. The organic layer was washed with brine, then dried overMgSO₄, and concentrated in vacuo to give 1.4 g (78%) of the desired3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a red oil. The crude product was used without furtherpurification. HRMS calcd. for C₁₈H₁₈F₇N₂O₂: 427.1256 [M+H]⁺, found:427.1251. ¹H NMR (CDCl₃) δ3.4-3.7 (m, 4H), 3.8 (dd, 1H), 4.3 (m, 1H),4.8 (m, 2H), 5.9 (tt, 1H), 6.1 (s, 1H), 6.2 (m, 2H), 7.0-7.2 (m, 4H),7.3 (t, 1H).

The3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolfrom EX-528C (50 mg, 0.12 mmol) was dissolved in 1 mL ofdichloromethane. Triethylamine (25 μL, 0.18 mmol) followed by4-fluorobenzene-sulfonyl chloride were added. The solution was stirredat room temperature for 5 hours, at which time HPLC analysis indicatedthat no free amine starting material remained. The reaction was quenchedwith water and filtered through pre-wetted celite eluting with ethylacetate. The solvent was evaporated, and the residue was purified byreverse phase HPLC eluting with 10% to 90% acetonitrile in water toafford 20.1 mg (29%) of the desired4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]benzenesulfonamideproduct as a yellow oil, which was greater than 98% pure by reversephase HPLC analysis. HRMS calcd. for C₂₄H₂₁F₈N₂O₄S: 585.1094 [M+H]⁺,found: 585.1083. ¹H NMR (CDCl₃) δ3.6 (m, 2H), 3.8 (dd, 1H), 4.3 (m, 1H),4.6 (s, 2H), 5.9 (tt, 1H), 6.4 (d. 1H), 6.5-6.6 (m, 3H), 6.9-7.4 (m.7H), 7.6 (m, 1H).

Additional examples ofN-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,-trifluoro-2-hydroxypropyl)amino]phenyl]aryl or alkylsulfonamide areprepared by one skilled in the art using similar methods, as shown inExample Table 26.

Example Table 26. N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]aryl or alkylsulfonamides.

Calculated Observed Example Mass Mass Number R_(SUB) [M + H]⁺ [M + H]⁺529 phenyl 567.1189 567.1198 530 3-methylphenyl 581.1345 581.1327 5313-trifluoromethylphenyl 635.1062 635.1066 532 3-nitrophenyl 612.1039612.1011 533 3-chloro-4-fluorophenyl 619.0705 619.0711 534 isopropyl533.1345 533.1359

EXAMPLE 535

4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]benzamide

3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane.Triethylamine (25 μL, 0.18 mmol) followed by 4-fluorobenzoyl chloridewere added. The solution was stirred at room temperature for 5 hours, atwhich time HPLC analysis indicated that no starting material remained.The reaction was quenched with water and filtered through pre-wettedcelite eluting with ethyl acetate. The solvent was evaporated, and theresidue was purified by reverse phase HPLC eluting with 10% to 90%acetonitrile in water to afford 15 mg (23%) of the desired4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]-phenyl]benzamideproduct as a yellow oil. which was greater than 98% pure by reversephase HPLC analysis. HRMS calcd. for C₂₅H₂₁F₈N₂O₃: 549.1424 [M+H]⁺,found: 549.1436. ¹H NMR (CDCl₃) δ3.6 (dd, 1H), 3.8 (dd, 1H), 4.4 (m,1H), 4.6 (s, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.8 (d, 1H), 7.0-7.4 (m,7H), 7.8 (m, 3H).

Additional examples ofN-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]carboxamidesare prepared by one skilled in the art using similar methods. as shownin Example Table 27.

Example Table 27. N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]carboxamides.

Example Calculated Observed Mass Number R_(SUB) Mass [M + H]⁺ [M + H]⁺536 phenyl 531.1589 531.1538 537 3-methoxylphenyl 561.1624 561.1625 538isobutoxy 527.1781 527.1768 539 3-pyridyl 532.1471 532.1458 540isopropyl 497.1675 497.1701

EXAMPLE 541

3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

The3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(50 mg, 0.12 mmol) was dissolved in 1 mL of dichloroethane. Acetic acid(8 μL, 0.14 mmol) followed by isobutyraldehyde (11.7 μL, 0.13 mmol) andsolid NaBH(OAc)₃ (37.3 mg, 0.18 mmol) were added. The solution wasstirred at room temperature for 18 hours. The reaction was filteredthrough pre-wetted celite eluting with ethyl acetate. The solvent wasevaporated, and the residue was purified by reverse phase HPLC elutingwith 10% to 90% acetonitrile in water to afford 16.1 mg (29%) of thedesired3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a yellow oil, which was greater pure by reverse phase HPLCanalysis. HRMS calcd. for C₂₂H₂₆F₇N₂O₂: 483.1883 [M+H]⁺, found:483.1932. ₁H NMR (CDCl₃) δ1.0 (m, 6H), 2.0 (m, 1H), 3.0 (m, 2H), 3.6(dd, 1H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (m, 2H), 5.9 (tt, 1H), 6.6 (d,1H), 6.7 (d, 1H), 6.9-7.4 (m, 6H).

Additional examples of3-[[3-(aralkylamino)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 28.

Example Table 28.1,1,1-trifluoro-3-[[3-(aralkylamino)pheny]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-2-propanols.

Calculated Observed Example Mass Mass Number R_(SUB) [M + H]⁺ [M + H]⁺542 phenyl 517.1726 517.1750 543 4-fluorophenyl 535.1632 535.1627 5443-(OCF₂CF₂H)-phenyl 633.1611 633.1653

EXAMPLE 545

N-(4-fluorophenyl)-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]urea

The3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane.Triethylamine (20 μL, 0.14 mmol) followed by 4-fluorophenyl isocyanate(14.6 μL 0.13 mmol) were added. The solution was stirred at roomtemperature for 18 hours. The reaction was filtered through pre-wettedcelite eluting with ethyl acetate. The solvent was evaporated, and theresidue was purified by reverse phase HPLC eluting with 10% to 90%acetonitrile in water to afford 26 mg (40%) of the desiredN-(4fluorophenyl)-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]ureaproduct as a yellow oil, which was greater than 95% pure by reversephase HPLC analysis. HRMS calcd. for C₂₅H₂₂F₈N₃O₃: 564.1533 [M+H]⁺,found: 564.1566. ¹H NMR (CDCl₃) δ3.7 (m, 2H), 4.1 (m, 1H), 4.7 (m, 2H),5.9 (tt, 1H), 6.6 (d, 1H), 6.9-7.4 (m, 11H), 7.5 (s, 1H), 7.8 (s, 1H).

Additional examples ofN-substituted-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]ureasare prepared by one skilled in the art using similar methods, as shownin Example Table 29.

Example Table 29. N-substituted-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]ureas.

Calculated Observed Example Mass Mass Number R_(SUB) [M + H]⁺ [M + H]⁺546 phenyl 546.1628 546.1655 547 3-methoxyphenyl 576.1733 576.1773 5483-trifluoromethylphenyl 614.1501 614.1518 549 isopropyl 512.1784512.1801

EXAMPLE 550

1,1,1-trifluoro-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][[3′-(trifluoromethyl)1,1′-biphenyl]-3-yl]amino]-2-propanol

3-Trifluoromethylbenzene boronic acid (35.4 mg, 0.233 mmol) wasdissolved in 640 mL of 2 M Na₂CO₃, and 630 mL of ethanol then 1.5 mL ofa stock solution of3-[(3-bromophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(0.105 M) and 10.9 mg/mL of Pd(PPh₃)₄ in toluene was added. Afterstirring at 105° C. for 5 hours, HPLC analysis indicated that thereaction had gone to completion. The reaction mixture was filteredthrough celite, evaporated, and the crude material purified by reversephase HPLC eluting with 40% to 90% acetonitrile in water to afford 40.5mg (44.7%) of the desired biphenyl aminopropanol product as an orangeoil. HRMS calcd. for C₂₅H₁₉F₁₀NO₂: 556.1334 [M+H]⁺, found: 556.1339. ¹HNMR (CDCl₃) δ3.60-3.73 (m, 1H), 3.95 (dd, 1H), 4.36-4.44 (m, 1H), 4.76(s, 2H), 5.87 (tt, 1H), 6.81 (dd, 1H), 6.95 (s, 1H), 7.03 (d, 1H),7.05-7.20 (m, 3H), 7.26-7.40 (m, 2H), 7.46-7.73 (m, 4H).

Additional examples of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][[3-aryl]phenyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 30.

Example Table 30. 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][[3-aryl]phenyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Example Mass Mass Number R_(SUB) [M + H]⁺ [M + H]⁺551 3,5-di(trifluoromethyl) 624.1208 624.1216 552 4-trifluoromethyl556.1334 556.1355 553 4-methylthio 534.1337 534.1366 5543-chloro-4-fluoro 540.0976 540.0957 555 3,5-dichloro-4-methoxy 586.0786586.0818 556 3-nitro 533.1311 533.1262 557 3,5-dichloro 556.0681556.0612 558 4-methoxy 518.1566 518.1533 559 3,4-difluoro 524.1272524.1249 560 2,3,4-trifluoro 542.1177 542.1152 561 3,4-dichloro 556.0681556.0698 562 3-methyl-4-methoxy 532.1722 532.1676 5633,5-dimethyl-4-(N,N- 559.2195 559.2182 dimethylamino) 564 H 488.1460488.1457 565 4-chloro 522.1071 522.1049 566 4-methyl 502.1617 502.1613567 2,4-dichloro 556.0681 556.0651 568 4-fluoro 506.1366 506.1336 5694-fluoro-3-methyl 520.1523 520.1494 570 2-trifluoromethyl 556.1334556.1286 571 3-methoxy 518.1566 518.1544 572 3-amino 503.1569 503.1593573 4-carboxy 532.1358 532.1329 574 4-tert-butyl 544.2087 544.2090

EXAMPLE 575

3-[[[4′-(methylsulfonyl)1,1′-biphenyl]-3-yl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

To solution of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][[4-methylthio)-phenyl]phenyl]amino]-1,1,1-trifluoro-2-propanolin 2 mL of trifluoroacetic acid was added 11 mL of 30% H₂O₂ (0.097mmol). After stirring at room temperature overnight, an additional 11 mLof 30% H₂O₂ (0.097 mmol) was added. After 5 hours, TLC analysisindicated that the reaction had gone to completion. The solvent wasremoved, and the residue was filtered through silica gel eluting with30% ethyl acetate in hexane. The material was evaporated to give 36.6 mg(100%) of the desired sulfone product as an oil which was 100% pure byreverse phase HPLC analysis. HRMS calcd. for C₂₅H₂₂F₇NO₄S: 566.1236[M+H]⁺, found: 566.1193. ¹H NMR (CDCl₃) δ3.04 (s, 3H), 3.66-3.79 (m,1H), 3.97 (d, 1H), 4.35-4.43 (m, 1H), 4.69-4.81 (m, 2H), 5.86 (dt, 1H),6.90 (d, 1H), 7.01(s, 1H), 7.05-7.18 (m, 4H), 7.31-7.40 (m, 2H), 7.60(d, 2H), 7.93 (d, 2H).

EXAMPLE 576

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile

EX-576A) A solution of 3-aminobenzonitrile (1.06 g, 9.1 mmol) and3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (2.00g, 9.01 mmol) wasdissolved in 25 mL of dichloroethane and acetic acid (536 mL, 9.37mmol), then solid NaB H(OAc)₃ (2.48 g, 11.7 mmol) was added. The mixturewas stirred at room temperature for 3 hours, then quenched with waterand extracted with dichloromethane. The organic layer was washed withsaturated NaHCO₃, then dried over MgSO₄, and evaporated. The crudeproduct was purified by MPLC on silica gel eluting with 20% to 30% ethylacetate in hexane to give 1.58 g (54%) of the desired3-[[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]benzonitrileproduct as a clear oil. ¹H NMR (CDCl₃) δ4.38 (s, 3H), 5.89 (dt, 1H),6.79 (t, 1H), 6.98 (d, 2H), 7.12-7.28 (m, 4H), 7.40 (t, 1H).

The benzonitrile (1.58 g, 4.88 mmol) from EX-576A and1,1,1-trifluoro-2,3-epoxy-propane (546 mL, 6.34 mmol) were dissolved in4 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (304 mg,0.49 mmol) was added, and the stirred solution was warmed to 50° C.overnight. The reaction was quenched with water and extracted withether. The ether layer was washed with brine, dried over MgSO₄ andevaporated. The crude product was purified by MPLC on silica gel elutingwith dichloromethane to give 1.61 g (76%) of the desired3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrileproduct as a clear oil, greater than 98% by reverse phase HPLC. HRMScalcd. for C₁₉H₁₅F₇N₂O₂: 437.1100 [M+H]⁺, found: 437.1097. ¹H NMR(CDCl₃) δ3.60-3.69 (m, 1H), 3.86 (d, 1H), 4.32 (bs, 1H), 4.69 (q, 2H),5.86 (dt, 1H), 6.85-6.95 (m, 2H), 6.97-7.01 (m, 2H), 7.04-7.12 (m, 2H),7.23-7.37 (m. 2H).

EXAMPLE 577

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(1H-tetrazol-5-yl)phenyl]amino]-1,1,1-trifluoro-2-propanol

To a solution of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile(76 mg, 0.17 mmol) in 2 mL of toluene was added trimethyltin azide (41mg, 0.20 mmol). The reaction mixture was heated to 105° C. and stirredovernight. TLC showed starting material to still be present soadditional trimethyltin azide (41 mg, 0.20 mmol) was added. The reactionmixture was stirred overnight at 105° C., cooled to room temperature,then THF (800 μL) and concentrated HCl (500 μL) were added. HPLCanalysis showed 2 peaks after 5 hours so additional concentrated HCl(200 μL) was added. After stirring overnight, HPLC analysis showed thereaction to be complete. The mixture was filtered through a celite plugand evaporated in vacuo. The residue was purified by reverse phase HPLCeluting with 10% to 90% acetonitrile in water to give 27.2 mg (33%) ofthe desired tetrazole product as an oil. HRMS calcd. for C₁₉H₁₆F₇N₅O₂:480.1270 [M+H]⁺, found: 480.1252. ¹H NMR (CDCl₃) δ3.66-3.99 (m, 2H),4.45-4.75 (m, 3H), 5.80 (dt, 1H), 6.49-6.70 (m, 1H), 6.95 (s, 1H),6.97-7.06 (m, 3H), 7.18-7.28 (m, 3H), 7.34 (s, 1H).

EXAMPLE 578

(4-Fluoro-3-methylphenyl)[3-[[[(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]methanone

To a solution of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile(100 mg, 0.23 mmol) in 1 mL of anhydrous THF under nitrogen was added4fluoro-3-methylphenylmagnesium bromide (0.81 mL of 1.0 M solution, 0.81mmol), and the mixture was stirred at room temperature overnight. HPLCanalysis of the reaction mixture showed the presence of startingmaterial so additional 4-fluoro-3-methylphenylmagnesium bromine (0.46mL, 0.41 mmol) was added. HPLC analysis 24 hours later showed thereaction to be complete. The reaction was quenched and acidified with 1N HCl. After hydrolysis of imine was complete by HPLC analysis, themixture was filtered through celite and evaporated. The crude productwas purified by reverse phase HPLC eluting with 10% to 90% acetonitrilein water to give 28.0 mg (22%) of the desired ketone product as an oil.HRMS calcd. for C₂₆H₂₁F₈NO₃: 548.1410 [M+H]⁺, found: 548.1441. ¹H NMR(CDCl₃) δ2.26 (s, 3H), 3.60-3.70 (m, 1H), 3.92 (d, 1H), 4.26-4.40 (m,1H), 4.68 (t, 2H), 5.87 (dt, 1H), 6.91-7.03 (m, 3H), 7.05-7.12 (m, 4H),7.26-7.35 (m, 2H), 7.43-7.52 (m, 1H), 7.63 (d, 1H).

Additional examples of (aryl-, alkyl- orcycloalkyl-)[3-[[[1,1,2,2-tetraflouroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]methanonesare prepared by one skilled in the are using similar methods, as shownin Example Table 31

Example Table 31. (Aryl-, alkyl- or cycloalkyl-)[3-[[[(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]methanones.

Example Calculated Observed Mass Number R_(SUB) Mass [M + H]⁺ [M + H]⁺579 phenyl 516.1410 516.1383 580 4-fluorophenyl 534.1315 534.1273 581cyclopentyl 508.1723 508.1675 582 isopropyl 482.1566 482.1576

EXAMPLE 583

α-phenyl-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]](3,3,3-trifluoro-2-hydroxypropyl)benzenemethanol

To a solution of phenyl[3-[[[(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]methanone(155.8 mg, 0.302 mmol) in 2.3 mL of methanol cooled to 5° C. was addedsolid NaBH₄ (34.5 mg, 0.912 mmol). HPLC analysis after 1 hour showed noketone starting material. The reaction was evaporated to dryness andpurified by reverse phase HPLC eluting with 50% to 90% acetonitrile inwater to give 35.6 mg (24%) of the desired alcohol product as an oil.HRMS calcd. for C₂₅H₂₂F₇NO₃: 518.1566 [M+H]⁺, found: 518.1563. ¹H NMR(acetone-d₆) δ3.56-3.73 (m, 1H), 3.92-4.06 (m, 1H), 4.40-4.55 (m, 1H),4.82 (s, 2H), 5.71 (s, 1H), 6.28-6.69 (m, 2H), 6.71-6.82 (m, 1H), 6.93(s, 1H), 7.07-7.51 (m, 10H).

Additional examples of α-alkyl-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][(3,3,3-trifluoro-2-hydroxypropyl)benzenemethanols areprepared by one skilled in the art using similar methods, as shown inExample Table 32.

Example Table 32. α-alkyl-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-[(3,3,3-trifluoro-2-hydroxypropyl)benzenemethanols

Example Calculated Mass Observed Mass Number R_(SUB) [M + H]⁺ [M + H]⁺584 isopropyl 484.1723 484.1725

EXAMPLE 585

Ethyl 3-[(3,3,3-trifluoro-2-hydroxypropyl)[[(3-trifluoromethoxy)phenyl]methyl]amino]benzoate

EX-585A) Ethyl 3-aminobenzoate (3.9 mL, 26 mmol) and3-trifluoromethoxy-benzaldehyde (4.91 g, 25.8 mmol) were dissolved in 65mL of dichloroethane and acetic acid (1.6 mL, 28 mmol), then solidNaBH(OAc)₃ (7.5 g, 34.2 mmol) was added. The mixture was stirred at roomtemperature overnight, then quenched with water and extracted withdichloromethane. The organic layer was washed with brine, then driedover MgSO₄, and evaporated to give 9.76 g (>100%) of the desired ethyl3[[[(3-trifluoromethyl)phenyl]methyl]amino]benzoate product as a yellowoil, which was greater than 95% pure by reverse phase HPLC analysis. ¹HNMR (CDCl₃) δ1.35 (t, 3H), 4.26-4.41 (m, 5H), 6.73 (d, 1H), 7.12 (d,1H), 7.15-7.25 (m, 2H), 7.25-7.43 (m, 4H).

The ethyl 3[[[(3-trifluoromethyl)phenyl]methyl]amino]benzoate (9.76 g,25.8 mmol) product from EX-585A and 1,1,1-trifluoro-2,3-epoxypropane(2.9 mL, 33.5 mmol) were dissolved in 25 mL of acetonitrile. Ytterbium(III) trifluoromethanesulfonate (1.6 g, 2.6 mmol) was added, and thestirred solution was warmed to 50° C. for 20 hours. The reaction wasquenched with water and extracted with dichloromethane. The organiclayer was washed with water and brine, then dried over MgSO₄. The crudeproduct was purified by column chromatography on silica gel eluting withdichloromethane to give 10.7 g (92%) of the desired ethyl3[(3,3,3-trifluoro-2-hydroxypropyl)[[(3-trifluoromethyl)phenyl]methyl]amino]benzoate product as a yellow oil. HRMS calcd. forC₂₀H₁₉NO₄F₆. 452.1297 [M+H]⁺, found: 452.1256. ¹H NMR (CDCl₃) δ1.32 (t,3H), 2.94-3.02 (m, 1H), 3.54-3.64 (m, 1H), 3.91 (d, 1H), 4.24-4.40 (m,3H), 4.69 (t, 2H), 6.86 (d, 1H), 7.05 (s, 1H), 7.07-7.14 (m, 2H),7.20-7.34 (m, 2H), 7.39-7.47 (m, 2H).

EXAMPLE 586

3-[(3,3,3-trifluoro-2-hydroxypropyl)[[(3-trifluoromethyl)phenyl]methyl]amino]benzoic Acid

Ethyl3-[(3,3,3-trifluoro-2-hydroxypropyl)[[(3-trifluoromethyl)phenyl]methyl]amino]-benzoatewas dissolved in 70 mL of THF and 35 mL of water. Lithium hydroxidemonohydrate (2.93 g, 69.8 mmol) was added, and the mixture was heated to45° C. under nitrogen overnight, at which time HPLC analysis indicatedthat the reaction had gone to completion. The mixture was acidified with1 N HCl to a pH of 3-4, then extracted with ethyl acetate several times,and the combined organic layers were dried over MgSO₄. The dried organiclayer was evaporated to give 11.2 g (100%) of the desired benzoic acidproduct as a pale orange oil, which was greater than 98% pure by reversephase HPLC analysis. HRMS calcd. for C₁₈H₁₅NO₄F₆. 424.0984 [M+H]⁺,found: 424.0991. ¹H NMR (acetone-d₆) δ3.68-3.81 (m, 1H), 3.99-4.09 (m,1H), 4.434.58 (m, 1H), 4.87 (s, 2H), 7.02 (d, 1H), 7.19 (d, 1H),7.22-7.40 (m, 4H), 7.40-7.49 (m, 2H).

EXAMPLE 587

3-[(3-phenoxyphenyl)[[3-(2-pyridinyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-587A) To a THF solution (8 mL) of 2-bromopyridine (1.30 g, 8.23 mmol)at −78° C. was added 1.6 M n-BuLi in hexanes (5.3 mL, 8.48 mmol). Theresulting dark red solution was stirred at −78° C. for 10 min, and asolution of 0.5 M ZnCl₂ in THF (18 mL, 9.0 mmol) was added giving alight brown slurry. After warming to room temperature,3-bromobenzaldehyde (0.816 mL, 7.0 mmol) and Pd(PPh₃)₄ (0.242 g, 0.21mmol) were added, and the mixture was stirred for 18 h at roomtemperature under argon. The reaction mixture was poured into 1 N HCl(30 mL) and washed with diethyl ether. The aqueous layer was neutralizedwith NaHCO₃ and extracted with diethyl ether. The solvent was removed invacuo to give the crude product as an oil. Purification by flashchromatography on silica gel eluting with 20% ethyl acetate in hexanegave 0.49 g (38%) of the desired 3-(2-pyridinyl)benzaldehyde product asa colorless oil. GCMS: m/z=183 [M⁺].

EX-587B) To a 1,2-dichloroethane (5 mL) solution of aldehyde (0.37 g,2.0 mmol) from EX-587A was added 3-phenoxyaniline (0.37 g, 2.0 mmol),NaB(OAc)₃H (0.55 g, 2.6 mmol) and acetic acid (0.12 mL, 2.0 mmol). Thecloudy solution was stirred at room temperature for 2 h. The reactionmixture was poured into water and extracted with dichloromethane. Theorganic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄)and evaporated to yield 0.70 g (100%) of the desiredN-3-(phenoxyphenyl)-[[3-(2-pyridinyl)phenyl]methyl]amine product as ayellow oil. HRMS: calcd. for C₂₄H₂₁N₂O: 353.1654 [M+H ]⁺, found:353.1660.

A THF (1 mL) solution of amine (0.47 g, 1.3 mmol) from EX-587B and1,1,1-trifluoro-2,3-epoxypropane (0.35 mL, 4.1 mmol) was placed in asealed vial and heated to 90° C. for 18 h with stirring. The solvent wasremoved in vacuo to give the crude product as an oil. Purification byflash chromatography on silica gel eluting with 20% ethyl acetate inhexane gave 0.026 g (4.2%) of the desired 3-[(3-phenoxyphenyl)[[3-(2-pyridinyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol productas a yellow oil. HRMS calcd. for C₂₇H₂₄N₂O₂F₃: 465.1790 [M+H]⁺, found:465.1798. ¹H NMR (CDCl₃) δ3.63 (dd, 1H), 3.73 (br s, 1H), 3.82 (dd, 1H),4.30 (m, 1H), 4.67 (d. 2H), 6.34 (dd, 1H), 6.44 (t, 1H), 6.52 (dd, 1H),6.92 (d, 2H), 7.02 (t, 1H), 7.12 (t, 1H), 7.2 (m, 4H), 7.38 (t, 1H),7.65 (d, 1H), 7.72 (d, 1H), 7.74 (d 1H), 7.84 (s, 1H), 8.62 (d, 1H).

EXAMPLE 588

3-[(3-phenoxyphenyl)[[3-[(3-trifluoromethyl)-2-pyridinyl]phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-588A) To a toluene (10 mL) solution of2-bromo-3-trifluoromethylpyridine (1.10 g. 4.87 mmol) was added3-formylphenylboronic acid (0.90 g, 6.0 mmol) and DMF (4 mL). To theresulting solution was added K₂CO₃ (1.67 g, 12.1 mmol) and Pd(PPh₃)₄(0.35 g, 0.30 mmol). The slurry was heated to reflux under argon for 18h. The cooled mixture was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried (MgSO₄) andevaporated to an oil. Purification by flash chromatography on silica geleluting with 20% ethyl acetate in hexane gave 0.55 g (45%) of thedesired 3-[(3-trifluoromethyl)-2-pyridinyl]benzaidehyde product as acolor-less oil which solidified upon standing. HRMS: calcd. forC₁₃H₉NOF₃: 252.0636 [M+H]⁺, found: 252.0639.

EX-588B) A mixture of solid 3-phenoxyaniline (2.96 g, 16 mmol) and1,1,1-trifluoro-2,3-epoxypropane (1.30 mL, 15.0 mmol) was placed in asealed tube and heated to 100° C. giving a dark solution. The stirredsolution was heated 18 h and cooled to give a dark oil. Purification byflash chromatography on silica gel eluting with dichloromethane gave3.15 g (71%) of the desired3-[(N-3-phenoxy-phenyl)amino]-1,1,1-trifluoro-2-propanol product as acolorless oil. Anal. calcd. for C₁₅H₁₄NO₂F₃.0.05 CH₂Cl₂: C, 59.92; H,4.71; N, 4.64. Found: C, 59.92; H, 4.53; N, 4.73; HRMS calcd. 298.1055[M+H]⁺, found: 298.1056.

To a 1,2-dichloroethane (8 mL) solution of aldehyde (0.55 g, 2.2 mmol)from EX-588A was added the amine (0.66 g, 2.2 mmol) from EX-588B,NaB(OAc)₃H (0.61 g, 2.9 mmol) and acetic acid (0.15 mL, 2.6 mmol). Thecloudy solution was stirred at room temperature for 4 h. The reactionmixture was poured into water and extracted with dichloromethane. Theorganic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄)and evaporated to give an oil. Purification by flash chromatography onsilica gel eluting with 20% ethyl acetate in hexane gave 0.33 g (29%) ofthe desired3-[(3-phenoxyphenyl)[[3-[(3-trifluoromethyl)-2-pyridinyl]phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a white foam, >97% pure by HPLC analysis. Anal. calcd. forC₂₈H₂₂N₂O₂F₆: C, 63.16; H, 4.16; N, 5.26. Found: C, 62.87; H, 4.02; N,5.33. HRMS: calcd. 533.1664 [M+H]⁺, found: 533.1658. ¹H NMR (C₆D₆) δ2.97(d, 1H), 3.26 (dd, 1H), 3.46 (dd, 1H), 3.77 (m, 1H), 4.22 (dd, 2H), 6.31(dd, 1H), 6.35 (dd, 1H), 6.40 (dd, 1H), 6.54 (t, 1H), 6.80 (t, 1H),6.9-7.0 (m, 7H), 7.26 (d, 1H), 7.33 (d, 1H), 7.40 (s, 1H), 8.17 (d, 1H).

Additional examples of3-[(3-phenoxyphenyl)[[3-(heteroaryl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 33.

Example Table 33. 3-[(3-phenoxyphenyl)[[3-(heteroaryl)phenyl]methyl]amino]- 1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 5893-methyl-pyridin-2-yl 479.1949 479.1946 590 pyridin-3-yl 465.1790465.1778 591 pyridin-4-yl 465.1790 465.1821

EXAMPLE 592

3-[(3-phenoxyphenyl)[[3-(2-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-592A) To a dioxane (20 mL) solution of 3-bromobenzaldehyde (0.63 mL,5.4 mmol) was added 2-(tributylstannyl)furan (1.89 mL, 6.00 mL) andPd(PPh₃)₂Cl₂ (0.21 g, 0.30 mmol). The mixture was heated to reflux underargon for 1.5 h. The cooled mixture was poured into a mixture ofsaturated KF and ethyl acetate and stirred 18 h. The slurry was filteredthrough celite. The organic layer was separated, washed with brine,dried (MgSO₄) and evaporated to an oil. Purification by flashchromatography on silica gel eluting with 5% ethyl acetate in hexanegave 0.80 g (86%) of the desired 3-(2-furanyl)benzaidehyde product as anyellow oil which solidified upon standing. MS: m/z=173.1 [M+H]⁺.

EX-592B) To a 1,2-dichloroethane (7 mL) solution of aldehyde (0.40 g,2.3 mmol) from EX-592A was added 3-phenoxyaniline (0.43 g, 2.3 mmol),NaB(OAc)₃H (0.64 g, 3.0 mmol) and acetic acid (0.15 mL, 2.6 mmol). Thecloudy solution was stirred at room temperature for 2 h. The reactionmixture was poured into water and extracted with dichloromethane. Theorganic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄)and evaporated to yield 0.74 g (94%) of the desiredN-(3-phenoxyphenyl)[[3-(2-furanyl)phenyl]methyl]amine product as anyellow oil which was used without further purification. MS: m/z=342.3[M+H]⁺.

To a dichloromethane (3 mL) solution of amine (0.74 g, 2.2 mmol) fromEX-592B was added 1,1,1-trifluoro-2,3-epoxypropane (0.28 mL, 3.3 mmol)and Yb(OTf)₃ (0.136 g, 0.20 mmol). The cloudy solution was stirred atroom temperature for 4 days, then diluted with diethyl ether, and washedwith water and brine. The organic layer was dried (MgSO₄) and evaporatedto an oil. Purification by flash chromatography on silica gel elutingwith 10% ethyl acetate in hexane gave an oil which was dissolved inEtOH, stripped and dried in vacuo to give 0.49 g (49%) of the desired3-[(3-phenoxyphenyl)[[3-(2-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a colorless oil, >98% pure by HPLC analysis. Anal. calcd. forC₂₆H₂₂NO₃F₃.0.5 EtOH.0.3 H₂O: C, 67.30; H, 5.35; N, 2.91. Found: C,67.12; H, 5.12; N, 2.89. HRMS calcd. 454.1630 [M+H]⁺, found: 454.1635.¹H NMR (C₆D₆) δ2.15 (d, 1H), 3.21 (dd, 1H), 3.50 (dd, 1H), 3.81 (m, 1H),4.24 (s, 2H), 6.09 (dd, 1H), 6.33 (d, 1H), 6.35 (d, 1H), 6.44 (dd, 1H),6.52 (t, 1H), 6.79 (m, 1H), 6.81 (s, 1H), 6.9-7.0 (m, 7H), 7.44 (d, 1H),7.47 (s, 1H).

Additional examples of3-[(3-phenoxyphenyl)[[4substituted-3-(2-furanyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 34.

Example Table 34. 3-[(3-phenoxyphenyl) [[4-substituted-3-(2-furanyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Mass Observed Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 593 F472.1536 472.1530 594 Me 468.1787 468.1783

EXAMPLE 595

3-[(3-phenoxyphenyl)[[3-(2-thienyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-595A) To a 1,2-dichloroethane (90 mL) solution of 3-bromobenzaldehyde(5.60 g, 30.3 mmol) was added 3-phenoxyaniline (5.60 g, 30.2 mmol),NaB(OAc)₃H (8.26 g, 39.0 mmol) and acetic acid (1.8 mL, 31. mmol). Thecloudy solution was stirred at room temperature for 1.5 h. The reactionmixture was poured into water and extracted with dichloromethane. Theorganic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄)and evaporated to yield 10.49 g (98%) of the desiredN-(3-phenoxyphenyl)[(3-bromophenyl)methyl]amine product as a light brownoil. ¹H NMR (CDCl₃) δ4.26 (s, 2H), 6.27 (s, 1H), 6.38 (d, 2H), 7.00 (d,2H), 7.13 (m, 2H), 7.19 (t, 1H), 7.26 (d, 1H), 7.30 (m, 2H), 7.38 (d,1H), 7.96 (s, 1H). The formation of the desired product was monitored bythe disappearance of the aldehyde peak (δ˜10) and the formation of thebenzyl peak (δ4.26) in the ¹H NMR spectrum.

EX-595B) To a dichloromethane (15 mL) solution of amine from EX-595A(6.01 g, 17.0 mmol) was added 1,1,1-trifluoro-2,3-epoxypropane (1.75 mL,20.3 mmol) and Yb(OTf)₃ (1.05 g, 1.69 mmol). The cloudy solution wasstirred at room temperature for 24 h, diluted with diethyl ether, andwashed with water and brine. The organic layer was dried (MgSO₄) andevaporated to an oil. Purification by flash chromatography on silica geleluting with 3-8% ethyl acetate in hexane gave an oil which wasdissolved in EtOH, stripped and dried in vacuo to give 4.71 g (60%) ofthe desired3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a colorless oil. Anal. calcd. for C₂₂H₁₉NO₂F₃Br.0.41 EtOH: C,56.49; H, 4.46; N, 2.89. Found: C, 56.15; H, 4.22; N, 2.92. HRMS calcd.466.0629 [M+H]⁺, found: 466.0598.

To a dioxane (5 mL) solution of aminopropanol from EX-595B (0.38 g, 0.82mmol) was added 2-(tributylstannyl)thiophene (0.29 mL, 0.90 mmol) andPd(PPh₃)₂Cl₂ (0.040 g, 0.057 mmol). The mixture was heated to refluxunder argon for 18 h. The cooled mixture was poured into a mixture of10% aq. KF and ethyl acetate and stirred 1 h. The slurry was filteredthrough celite. The organic layer was separated, washed with brine,dried (MgSO₄) and evaporated to an oil. Purification by flashchromatography on silica gel eluting with 5-15% ethyl acetate in hexanegave an oil which was dissolved in EtOH, stripped and dried in vacuo togive 0.17 g (45%) of the desired3-[(3-phenoxy-phenyl)[[3-(2-thienyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a colorless oil. Anal. calcd. for C₂₆H₂₂NO₂F₃S.0.62 EtOH: C,65.69; H, 5.20; N, 2.81. Found: C, 65.36; H, 4.84; N, 2.81. HRMS calcd.470.1402 [M+H]⁺, found: 470.1392. ¹H NMR(CDCl₃) δ2.60(brs, 1H), 3.64(dd. 1H), 3.89 (dd, 1H), 4.37 (m, 1H), 4.68 (s, 2H), 6.42 (dd, 1H), 6.45(t, 1H), 6.55 (dd, 1H), 6.98 (dd, 2H), 7.1 (m, 3H), 7.20 (t, 1H),7.2-7.3 (m, 5H), 7.43 (s, 1H), 7.52 (d, 1H).

EXAMPLE 596

3-[(3-phenoxyphenyl)[[3-(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

To a THF (4 mL) solution of3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(0.60 g, 1.3 mmol) from EX-595B was added benzyl-magnesium bromide inTHF (2.0 mL, 2.0 M, 4.0 mmol) and Pd(PPh₃)₄. The resulting yellowsolution was refluxed under N₂ for 18 h. The cooled solution was pouredinto saturated aq. NH₄Cl, extracted with ethyl acetate, dried (MgSO₄)and evaporated to an oil. Purification by flash chromatography on silicagel eluting with 15% ethyl acetate in hexane gave an oil which wasdissolved in EtOH, stripped and dried in vacuo to give 0.39 g (62%) ofthe desired3-[(3-phenoxyphenyl)[[3-(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a colorless oil. Anal. calcd. for C₂₉H₂₆NO₂F₃.0.4 ETOH: C,72.17; H, 5.77; N, 2.82. Found: C, 72.17; H, 5.42; N, 2.83. HRMS calcd.478.1994 ([M+H]⁺, found: 478.1984. ¹H NMR (C₆D₆) δ1.58 (d, 1H), 3.22(dd, 1H), 3.46 (dd, 1H), 3.69 (s, 2H), 3.73 (m, 1H), 4.18 (s, 2H), 6.34(dd, 1H), 6.47 (dd, 1H), 6.53 (t, 1H), 6.8-7.1 (m 15H).

Additional examples of 3[(3-phenoxyphenyl)[[3-(alkyl-orcycloalkyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are preparedby one skilled in the art using similar methods, as shown in ExampleTable 35.

Example Table 35. 3-[(3-phenoxyphenyl)[[3-(alkyl- or cycloalkyl-)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. R_(SUB) Mass [M + H]⁺ [M + H]⁺ 5973-methylbutyl 458.2307 458.2295 598 2-methylpropyl 444.2150 444.2157 599cyclopropyl 428.1837 428.1806

EXAMPLE 600

3-[(3-phenoxyphenyl)[[2′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]methyl]amino]-1,1,1-trifluoro-2-propanol

To a toluene (8 mL) solution of3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol(0.51 g, 1.1 mmol) from EX-595B was added2-(tri-fluoromethyl)phenylboronic acid (0.33 g, 1.7 mmol) and DMF (3mL). To the resulting solution was added K₂CO₃ (0.31 g, 2.2 mmol) andPd(PPh₃)₄ (0.060 g, 0.05 mmol). The slurry was heated to reflux underargon for 18 h. The cooled mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with brine, dried(MgSO₄) and evaporated to an oil. Purification by flash chromatographyon silica gel eluting with 20% ethyl acetate in hexane gave an oil whichwas dissolved in EtOH, stripped and dried in vacuo to give 0.32 g (55%)of the desired 3-[(3-phenoxyphenyl)[[(2′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]methyl]amino]-1,1,1-tri-fluoro-2-propanolproduct as a colorless oil. Anal. calcd. for C₂₉H₂₃NO₂F₆.0.8 EtOH: C,64.67; H, 4.93; N, 2.46. Found: C, 64.53; H, 4.69; N, 2.49. HRMS calcd.532.1711 [M+H]⁺, found: 532.1708. ¹H NMR (C₆D₆) δ1.72 (d, 1H), 3.17 (dd,1H), 3.46 (dd, 1H), 3.72 (m, 1H), 4.23 (s, 2H), 6.33 (dd, 1H), 6.43 (dd,1H), 6.52 (t, 1H), 6.82 (m, 2H), 6.9-7.1 (m, 11H), 7.43 (d, 1H).

EXAMPLE 601

3-[(3-phenoxyphenyl)[[3-(3-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-601A) To a toluene (10 mL) solution of 3-bromofuran (0.54 mL, 6.0mmol) was added 3-formylphenylboronic acid (1.00 g, 6.7 mmol) and DMF (4mL). To the resulting solution was added K₂CO₃ (1.85 g, 13.4 mmol) andPd(PPh₃)₄ (0.40 g, 0.35 mmol). The slurry was heated to reflux underargon for 2 h. The cooled mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with brine, dried(MgSO₄) and evaporated to an oil. Purification by flash chromatographyon silica gel eluting with 5% ethyl acetate in hexane gave 0.10 g (10%)of the desired 3-(3-furanyl)benzaldehyde product as a yellow oil. MS:m/Z=173.0 [M+H]⁺.

EX-601B) To a 1,2-dichloroethane (3 mL) solution of the aldehyde (0.10g, 0.58 mmol) from EX-601A was added 3-phenoxyaniline (0.11 g, 0.59mmol), NaB(OAc)₃H (0.16 g, 0.75 mmol) and acetic acid (0.040 mL, 0.70mmol). The cloudy solution was stirred at room temperature for 2 h. Thereaction mixture was poured into water and extracted withdichloromethane. The organic layer was washed with saturated NaHCO₃ andbrine, dried (MgSO₄) and evaporated to yield 0.20 g (100%) of thedesired N-3-phenoxyphenyl)-[[3-(3-furanyl)phenyl]methyl]amine product asa yellow oil which was used without further purification. ¹H NMR (CDCl₃)δ4.1 (br s, 1H), 4.30 (s, 2H), 6.29 (d, 1H), 6.32 (dd, 1H), 6.39 (dd,1H), 6.66 (s, 1H), 6.95-7.05 (m, 4H), 7.2-7.5 (m, 7H), 7.70 (s, 1H). Theformation of the desired product was monitored by the disappearance ofthe aldehyde peak (δ˜10) and the formation of the benzyl peak (δ4.30) inthe ¹H NMR spectrum.

To a CH₃CN (2 mL) solution of amine (0.20 g, 0.58 mmol) from EX-601B wasadded 1,1,1-trifluoro-2,3-epoxypropane (0.10 mL, 1.2 mmol) and Yb(OTf)₃(0.035 g, 0.056 mmol). The cloudy solution was stirred in a sealed flaskat 40° C. After 18 h, additional 1,1,1-trifluoro-2,3-epoxypropane (0.20mL, 2.4 mmol) and Yb(OTf)₃ (0.035 g, 0.056 mmol) were added, and themixture was heated an additional 4 h, diluted with diethyl ether andwashed with water and brine. The organic layer was dried (MgSO₄) andevaporated to an oil. Purification by flash chromatography on silica geleluting with 10% ethyl acetate in hexane gave an oil which was dissolvedin EtOH, stripped and dried in vacuo to give 0.14 g (53%) of the desired3-[(3-phenoxyphenyl)[[3-(3-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol productas a colorless oil, >99% pure by HPLC analysis. Anal. calcd. forC₂₆H₂₂NO₃F₃.0.3 EtOH: C, 68.37; H, 5.13; N, 3.00. Found: C, 68.29; H,5.09; N, 2.99. HRMS calcd. 454.1630 [M+H]⁺, found: 454.1635. ¹H NMR(C₆D₆) δ1.62 (d, 1H), 3.18 (dd, 1H), 3.48 (dd, 1H), 3.74 (m, 1H), 4.22(s, 2H), 6.32 (dd, 1H), 6.35 (m, 1H), 6.44 (dd, 1H), 6.52 (t, 1H), 6.78(m, 1H), 6.82 (d, 1H), 6.9-7.1 (m, 9H), 7.37 (s, 1H).

EXAMPLE 602

3-[(3-phenoxyphenyl)[[3-(1-methyl-1H-pyrrol-2-yl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-602A) To solution of N-methylpyrrole (0.97 mL, 11 mmol) in Et₂O (20mL) was added neat TMEDA (1.5 mL, 10 mmol) and 1.6 M n-BuLi in hexanes(6.3 mL, 10 mmol). The solution was healed to reflux under N₂ for 1 hand then cooled to −78° C. A 1.0 M solution of Me₃SnCl in THF was addedover 15 min, and the resulting solution stirred for 30 min at −78° C.After warming to room temperature, 3-bromo-benzaldehyde (0.70 mL, 6.0mmol), Pd(PPh₃)₂Cl₂ (0.25 g, 0.35 mmol) and dioxane (10 mL) were added.The slurry was heated to reflux for 18 h. The cooled mixture was pouredinto a mixture of saturated KF and ethyl acetate and stirred 15 min. Theslurry was filtered through celite. The organic layer was separated,washed with brine, dried (MgSO₄) and evaporated to an oil. Purificationby flash chromatography on silica gel eluting with 5% ethyl acetate inhexane gave 0.45 g (24%) of the desired3-(1-methyl-1H-pyrrol-2-yl)benzaldehyde product as a yellow oil. MS:m/z=186.2 [M+H]⁺.

EX-602B) To a 1,2-dichloroethane (10 mL) solution of aldehyde (0.45 g,2.4 mmol) from EX-602A was added 3-phenoxyaniline (0.45 g, 2.4 mmol),NaB(OAc)₃H (0.67 g, 3.2 mmol) and acetic acid (0.15 mL, 2.4 mmol). Thecloudy solution was stirred at room temperature for 2 h. The reactionmixture was poured into water and extracted with dichloromethane. Theorganic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄)and evaporated to yield 0.67 g (79%) of the desiredN-(3-phenoxyphenyl)[[3-(1-methyl-1H-pyrrol-2-yl)phenyl]methyl]amineproduct as a yellow oil which was used without further purification. ¹HNMR (CDCl₃) δ3.60 (s, 3H), 4.15 (br s, 1H), 4.35 (s, 2H), 6.2-6.4 (m,5H), 6.67 (s, 1H), 7.00-7.05 (m, 4H), 7.1-7.2 (m, 6H). The formation ofthe desired product was monitored by the disappearance of the aldehydepeak (δ˜10) and the formation of the benzyl peak (δ4.35) in the ¹H NMRspectrum.

To a CH₃CN (2 mL) solution of amine (0.67 g, 1.9 mmol) from EX-602B wasadded 1,1,1-trifluoro-2,3-epoxypropane (0.33 mL. 3.8 mmol) and Yb(OTf)₃(0.120 g, 0.19 mmol). The cloudy solution as stirred in a sealed flaskat 40° C. for 18 h. The cooled reaction mixture was diluted with diethylether and washed with water and brine. The organic layer was dried(MgSO₄) and evaporated to an oil. Purification by flash chromatographyon silica gel eluting with 10% ethyl acetate in hexane gave an oil whichwas dissolved in EtOH, stripped and dried in vacuo to give 0.57 (66%) ofthe desired3-[(3-phenoxyphenyl)[[3-(1-methyl-1H-pyrrol-2-yl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a colorless oil, >99% pure by HPLC analysis.

Anal. calcd. for C₂₇H₂₅N₂O₂F₃.0.9 EtOH: C, 68.10; H, 6.03; N, 5.51.Found: C, 68.36; H, 5.94; N, 5.65. HRMS calcd. 467.1946 [M+H]⁺, found:467.1950. ¹H NMR(C₆D₆) δ2.01(d, 1H), 2.97 (s, 3H), 3.21 (dd, 1H), 3.49(dd, 1H), 3.78 (m, 1H), 4.28 (s, 2H), 6.3-6.4 (m, 4H), 6.45 (dd, 1H),6.53 (t, 1H), 6.8-7.1 (m, 10H).

EXAMPLE 603

3-[(3-phenoxyphenyl)[[3-(2-pyrimidinyl)phenyl]methyl]amino]1,1,1-trifluoro-2-propanol

EX-603A) To a toluene (15 mL) solution of 2-chloropyrimidine (1.00 g,8.7 mmol) was added 3-formylphenylboronic acid (1.42 g, 9.5 mmol) andDMF (8 mL). To the resulting solution was added K₂CO₃ (2.63 g, 19.0mmol) and Pd(PPh₃)₄ (0.52 g, 0.45 mmol). The slurry was heated to refluxunder argon for 18 h. The cooled mixture was poured into water andextracted with ethyl acetate. The organic layer was washed with brine,dried (MgSO₄) and evaporated to an oil. Purification by flashchromatography on silica gel eluting with 20% ethyl acetate in hexanegave 0.63 g (39%) of the desired 3-(2-pyrimidinyl)benzaldehyde productas a brown oil which solidified upon standing. MS: m/z=185.1 [M+H]⁺,

EX-603B) To a 1,2-dichloroethane (10 mL) solution of aldehyde (0.62 g,3.4 mmol) from EX-603A was added 3-phenoxyaniline (0.62 g, 3.4 mmol),NaB(OAc)₃H (0.93 g, 4.4 mmol) and acetic acid (0.20 mL, 3.4 mmol). Thecloudy solution was stirred at room temperature for 2 h. The reactionmixture was poured into water and extracted with dichloromethane. Theorganic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄)and evaporated to yield 1.19 g (99%) of the desiredN-(3-phenoxyphenyl)[[3-(2-pyrimidinyl)phenyl]methyl]amine product as abrown oil which was used without further purification. MS: m/z=354.2[M+H]⁺.

To a CH₃CN (4 mL) solution of amine (1.19 g, 3.4 mmol) from EX-603B wasadded 1,1,1-trifluoro-2,3-epoxypropane (0.585 mL, 6.8 mmol) and Yb(OTf)₃(0.112 g, 0.18 mmol). The cloudy solution was stirred in a sealed flaskat 40° C. After 18 h, more 1,1,1-trifluoro-2,3-epoxypropane (0.585 mL,6.8 mmol) and Yb(OTf)₃ (0.112 g, 0.18 mmol) were added, and the slurrywas heated an additional 4 h. The cooled reaction mixture was dilutedwith diethyl ether and washed with water and brine. The organic layerwas dried (MgSO₄) and evaporated to an oil. Purification by silica gelflash chromatography eluting with 25% ethyl acetate in hexane gave anoil which was dissolved in EtOH, concentrated and dried in vacuo to give0.33 g (21%) of the desired3-[(3-phenoxyphenyl)[[3-(2-pyrimidinyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a pale yellow oil, >99% pure by HPLC analysis. Anal. calcd.for C₂₆H₂₂N₃O₂F₃.0.5 EtOH: C, 66.39; H, 5.16; N, 8.60. Found: C, 66.26;H, 4.85; N, 8.60. HRMS calcd. 466.1742 [M+H]⁺, found: 466.1724. ¹H NMR(C₆D₆) δ2.28 (br s, 1H), 3.27 (dd, 1H), 3.50 (dd, 1H), 3.78 (m, 1H),4.26 (m, 2H), 6.08 (t, 1H), 6.39 (dd, 1H), 6.52 (t, 1H), 6.75 (m, 1H),6.9-7.0 (m, 6H), 7.18 (t, 1H), 8.12 (d, 2H), 8.58 (s, 1H), 8.66 (d, 1H).

EXAMPLE 604

3-[(3-phenoxyphenyl)[[3-(2-furanyl)-4-(4-morpholinyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-604A) To a pyridine (15 mL) solution of 3-bromo-4-fluorobenzaldehyde(1.0 g, 4.9 mmol) was added morpholine (0.5 mL, 5.7 mmol) and K₂CO₃(0.69 g, 5.0 mmol), and the slurry was refluxed for 18 h. The solventwas removed, and the residue was partitioned between ethyl acetate andwater. The organic layer was separated, dried (MgSO₄) and evaporated toa yellow oil. Purification by flash chromatography on silica gel elutingwith 15% ethyl acetate in hexane gave 0.77 g (58%) of the desired3-bromo-4-(4-morpholinyl)benzaldehyde product as an white solid. ¹H NMR(CDCl₃) δ3.18 (m, 4H), 3.90 (m, 4H), 7.10 (d, 1H), 7.78 (d, 1H), 8.07(s, 1H), 9.83 (s, 1H).

EX-604B) To a dioxane (8 mL) solution of the aldehyde from EX-604A (0.77g, 2.8 mmol) was added 2-(tributylstannyl)furan (1.07 mL, 3.42 mmol) andPd(PPh₃)₂Cl₂ (0.12 g, 0.17 mmol). The mixture was heated to reflux underargon for 18 h. The cooled mixture was poured into a mixture ofsaturated aq. KF and ethyl acetate and stirred 3 h. The slurry wasfiltered through celite. The organic layer was separated, washed withbrine, dried (MgSO₄) and evaporated to a yellow oil. Purification bysilica gel flash chromatography eluting with 20% ethyl acetate in hexanegave 0.61 g (84%) of the desired3-(2-furanyl)-4-(4-morpholinyl)benzaldehyde product as a yellow oil. MS:m/z=258.1 [M+H]⁺.

To a 1,2-dichloroethane (6 mL) solution of aldehyde (0.59 g, 2.0 mmol)from EX-604B was addedN-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.50 g, 1.9mmol), NaB(OAc)₃H (0.52 g, 2.5 mmol) and acetic acid (0.12 mL, 2.1mmol). The cloudy solution was stirred at room temperature for 18 h. Thereaction mixture was poured into water and extracted withdichloromethane. The organic layer was washed with saturated NaHCO₃ andbrine, dried (MgSO₄) and evaporated to give an oil. Purification byflash chromatography on silica gel eluting with 15% ethyl acetate inhexane gave 0.25 g (25%) of the desired3-[(3-phenoxyphenyl)[[3-(2-furanyl)-4(4-morpholinyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a white foam, >99% pure by HPLC analysis. Anal. calcd. forC₃₀H₂₉N₂O₄F₃: C, 66.91: H, 5.43; N, 5.20. Found: C, 66.54; H, 5.67; N,5.02. HRMS: calcd. 539.2187 [M+H]⁺, found: 539.2158. ¹H NMR (C₆D₆) δ1.73(d, 1H), 2.55 (m, 4H), 3.23 (dd, 1H), 3.50 (dd, 1H), 3.52 (m, 4H), 3.75(m, 1H), 4.25 (s, 2H), 6.21 (dd, 1H), 6.36 (dd, 1H), 6.34 (dd, 1H), 6.56(t, 1H), 6.69 (d, 1H), 6.8 (m, 2H), 6.9-7.0 (m, 5H), 7.09 (t, 1H), 7.22(d, 1H), 7.34 (d, 1H).

EXAMPLE 605

3-[(3-phenoxyphenyl)[[3-(2-pyrimidinyloxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-605A) A slurry of 3-hydroxybenzaldehyde (1.22 g, 10 mmol),2-chloropyrimidine (1.14 g, 10 mmol) and K₂CO₃ (1.65 g, 12 mmol) in DMSO(20 mL) was heated to 100° C. for 1 h. The cooled mixture was pouredinto water and extracted with Et₂O. The organic layer was washed with2.5 N NaOH, 1 N HCl, saturated NaHCO₃ and brine, dried (MgSO₄) andevaporated to yield 1.42 g (71%) of the desired3-(2-pyrimidinyloxy)benzaldehyde product as a white solid which was usedwithout further purification. ¹H NMR (C₆D₆) δ7.12 (t, 1H), 7.54 (m, 1H),7.66 (t, 1H), 7.78 (m, 1H), 7.83 (m, 1H), 8.64 (d, 2H), 10.05 (s, 1H).

To a 1,2-dichloroethane (10 mL) solution of aldehyde (0.56 g, 2.8 mmol)from EX-605A was addedN-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.83 g, 2.8mmol), NaB(OAc)₃H (0.77 g, 3.6 mmol) and acetic acid (0.84 mL, 15 mmol).The cloudy solution was stirred at room temperature for 18 h. Thereaction mixture was poured into water and extracted withdichloromethane. The organic layer was washed with saturated NaHCO₃ andbrine, dried (MgSO₄) and evaporated to give an oil. Purification byflash chromatography on silica gel eluting with 2% methanol in CH₂Cl₂gave an oil which was dissolved in EtOH, stripped and dried in vacuo togive 0.28 g (21%) of the desired3[(3-phenoxyphenyl)[[3-(2-pyrimidinyloxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a colorless oil, >99% pure by HPLC analysis. Anal. calcd. forC₂₆H₂₂N₃O₃F₃.0.4 EtOH: C, 64.39; H, 4.92; N, 8.41. Found: C, 64.22; H,4.87; N, 8.53. HRMS calcd. 482.1692 [M+H]⁺, found: 482.1698. ¹H NMR(C₆D₆) δ3.12 (d, 1H), 3.16 (dd, 1H), 3.49 (d, 1H), 3.79 (m, 1H), 4.12(dd, 1H), 5.88 (t, 1H), 6.31 (dd, 1H), 6.41 (dd, 1H), 6.51 (t, 1H), 6.65(t, 1H), 6.80 (t, 1H), 6.85-7.05 (m, 8H), 7.82 (d, 2H).

EXAMPLE 606

3-[(3-phenoxyphenyl)[([1,1′-biphenyl]-3-ylmethyl)amino]-1,1,1-trifluoro-2-propanol

EX-606A) To an ethylene glycol dimethyl ether (10 mL) solution of3-bromo-benzaldehyde (0.63 mL, 5.4 mmol) was added phenylboronic acid(0.73 g, 6.0 mmol), 2 M Na₂CO₃ (10 mL) and Pd(PPh₃)₄ (0.35 g, 0.30mmol). The slurry was heated to reflux under argon for 18 h. The cooledmixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried (MgSO₄) and evaporated to anoil. Purification by flash chromatography on silica gel eluting with 15%ethyl acetate in hexane gave 0.77 g (98%) of the desired[(1,1′-biphenyl)-3-yl]-carboxaldehyde product as a colorless oil whichsolidified upon standing. ¹H NMR (C₆D₆) δ7.45 (m, 3H), 7.65 (m, 3H),7.70 (dd, 2H), 8.15 (m, 1H), 10.13 (s, 1H).

EX-606B)To a 1,2-dichloroethane (12 mL) solution of aldehyde (0.77 g,4.2 mmol) from EX-606A was added 3-phenoxyaniline (0.78 g, 4.2 mmol),NaB(OAc)₃H (1.16 g, 5.5 mmol) and acetic acid (0.25 mL, 4.2 mmol). Thecloudy solution was stirred at room temperature for 2 h. The reactionmixture was poured into water and extracted with dichloromethane. Theorganic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄)and evaporated to yield 1.49 g (100%) of the desiredN-(3-phenoxyphenyl)([1,1′-biphenyl]-3-ylmethyl)amine product as acolorless oil which was used without further purification. ¹H NMR(CDCl₃) δ4.35 (s, 2H), 6.35 (m, 2H), 6.44 (d, 1H), 6.97 (d, 2H), 7.05(t, 1H), 7.12 (t, 1H), 7.3-7.4 (m, 7H), 7.49 (d, 1H), 7.56 (m, 3H). Theformation of the desired product was monitored by the disappearance ofthe aldehyde peak (δ˜10) and the formation of the benzyl peak (δ4.35) inthe ¹H NMR spectrum.

To a CH₃CN (4 mL) solution of amine (1.48 g, 4.2 mmol) from EX-606B wasadded 1,1,1-trifluoro-2,3-epoxypropane (0.475 mL, 5.5 mmol) and Yb(OTf)₃(0.26 g, 0.42 mmol). The cloudy solution was stirred in a sealed flaskat 40° C. for 18 h. The cooled reaction mixture was diluted with diethylether and washed with water and brine. The organic layer was dried(MgSO₄) and evaporated to an oil. Purification by flash chromatographyon silica gel eluting with 10% ethyl acetate in hexane gave an oil whichwas dissolved in EtOH, stripped and dried in vacuo to give 0.65 g (34%)of the desired3-[(3-phenoxyphenyl)[([1,1′-biphenyl]-3-ylmethyl)amino]-1,1,1-trifluoro-2-propanolproduct as a colorless oil which solidified upon standing, >99% pure byHPLC analysis. Anal. calcd. for C₂₈H₂₄NO₂F₃.0.05 CH₂Cl₂: C, 72.03; H,5.19; N, 2.99. Found: C, 71.67; H, 5.10; N, 2.94. HRMS calcd. 464.1837[M+H]⁺, found: 464.1834. ¹H NMR (C₆D₆) δ1.43 (d, 1H), 3.17 (dd, 1H),3.46 (dd, 1H 3.70 (m, 1H), 4.26 (s, 2H), 6.32 (dd, 1H), 6.44 (dd, 1H),6.52 (t, 1H), 6.77 (m, 1H), 6.85-6.95 (m, 5H), 7.1 (m, 3H), 7.16 (t,2H), 7.26 (s, 1H), 7.27 (d, 1H), 7.40 (dd, 2H).

EXAMPLE 607

3-[(3-phenoxyphenyl)[[3-cyclopentylphenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-607A) To a 1,2-dichloroethane (12 mL) solution of3-cyclopentylbenzaldehyde (0.69 g, 4.0 mmol; P. L. Ornstein et al., J.Med. Chem. 1998, 41, 358-378) was added 3-phenoxyaniline (0.73 g, 4.0mmol), NaB(OAc)₃H (1.08 g, 5.1 mmol) and acetic acid (0.24 mL, 4.2mmol). The cloudy solution was stirred at room temperature for 2 h. Thereaction mixture was poured into water and extracted withdichloromethane. The organic layer was washed with saturated NaHCO₃ andbrine, dried (MgSO₄) and evaporated to an oil. Purification by flashchromatography on silica gel eluting with 10% ethyl acetate in hexanegave 0.30 g (22%) of the desiredN-(3-phenoxyphenyl)[[3-cyclopentylphenyl]methyl]amine product as acolorless oil. ¹H NMR (CDCl₃) δ1.55 (m, 2H), 1.63 (m, 2H), 1.78 (m, 2H),2.02 (m, 2H), 2.94 (m, 1H), 4.10 (m, 1H), 4.22 (m, 2H), 6.35 (m, 3H),7.0-7.2 (m, 10H). The formation of the desired product was monitored bythe disappearance of the aldehyde peak (δ˜10) and the formation of thebenzyl peak (δ4.22) in the ¹H NMR spectrum.

To a CH₃CN (0.9 mL) solution of amine (0.30 g, 0.87 mmol) from EX-607Awas added 1,1,1-trifluoro-2,3-epoxypropane (0.15 mL, 1.7 mmol) andYb(OTf)₃ (0.080 g, 0.13 mmol). The cloudy solution was stirred in asealed flask at 50° C. for 18 h. The cooled reaction mixture was dilutedwith diethyl ether and washed with water and brine. The organic layerwas dried (MgSO₄) and evaporated to an oil. Purification by flashchromatography on silica gel eluting with 10% ethyl acetate in hexanegave an oil which was dissolved in EtOH, stripped and dried in vacuo togive 0.19 g (48%) of the desired3-[(3-phenoxyphenyl)[[3-cyclopentylphenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a colorless oil which solidified upon standing, >99% pure byHPLC analysis. Anal. calcd. for C₂₇H₂₈NO₂F₃.0.4 EtOH: C, 70.45; H, 6.47;N, 2.96. Found: C, 70.21; H, 6.39; N, 2.94. HRMS calcd. 456.2150 [M+H]⁺.found: 456.2143. ¹H NMR (C₆D₆) δ1.43 (m, 4H), 1.58 (m, 2H), 1.62 (d,2H), 1.85 (m, 2H), 2.71 (m, 1H), 3.22 (dd, 1H), 3.49 (dd, 1H), 3.73 (m,1H), 4.26 (s, 2H), 6.35 (dd, 1H), 6.43 (dd, 1H), 6.55 (t, 1H), 6.8 (m,2H), 6.95-7.05 (m, 8H).

EXAMPLE 608

3-[(3-phenoxyphenyl)[[3-(tetrahydro-2-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-608A) Trifluoromethanesulfonic anhydride (2.0 mL, 11.9 mmol) wasadded dropwise over 5 minutes to a slurry of 3-hydroxybenzaldehyde (1.11g, 9.09 mmol) in dichloromethane (40 mL) at −78° C. To this slurry wasadded neat N,N-di-isopropyl-ethylamine (2.4 mL, 13.8 mmol) dropwise over5 min, and the resulting yellow solution was allowed to warm to roomtemperature. After 30 min at room temperature, the dark solution wasdiluted with dichloromethane and washed with 2.5 N NaOH, 1 N HCl,saturated NaHCO₃ and brine. The organic layer was dried (MgSO₄) andevaporated to give a red oil. Purification by flash chromatography onsilica gel eluting with 10% ethyl acetate in hexane gave 1.70 g (74%) ofthe desired triflate ester product as a pale yellow oil. MS: m/z=254[M+H]⁺.

EX-608B) To a mixture of Pd₂(dba)₃ (120 mg, 0.13 mmol) and P(o-tolyl)₃(150 mg, 0.50 mmol) in toluene (15 mL) was added the triflate ester fromEX-608A (1.70 g, 6.7 mmol), N,N-di-isopropylethylamine (3.50 mL, 20.1mmol) and 2,3-dihydrofuran (2.53 mL, 33.5 mmol). The solution was heatedto 70° C. in a sealed flask under argon for 18 h. The cooled solutionwas then diluted with ethyl acetate and washed with water, 1 N HCl,saturated NaHCO₃ and brine.

The organic layer was dried (MgSO ₄) and evaporated to give a red oil.The major product was isolated by flash chromatography on silica geleluting with 10% ethyl acetate in hexane and gave 0.72 g (62%) of thedesired 3-(dihydro-2-furanyl)benzaldehyde product as a cloudy yellowoil. MS: m/z=175.1 [M+H]⁺.

EX-608C) A THF (15 mL) solution of the aldehyde from EX-608B (0.70 g,4.0 mmol) and 2,6-lutidine (0.46 mL, 4.0 mmol) was stirred in a hydrogenatmosphere (50 psi) in the presence of 10% Pd/C (0.29 g) for 18 h atroom temperature. The slurry was filtered through celite, and thesolvent was removed. The residue was taken up in ethyl acetate andwashed with 1 N HCl and brine. The organic layer was dried (MgSO₄) andevaporated to give 0.50 g (70%) of the desired3-(tetrahydro-2-furanyl)phenylmethanol product as a yellow oil. Theformation of the desired product was monitored by the disappearance ofthe aldehyde (δ˜10) and olefin peaks in the ¹H NMR spectrum.

EX-608D) A slurry of the phenylmethanol product from EX-608C (0.50 g,2.8 mmol) and MnO₂ (2.10 g, 24.3 mmol) in dichlormethane (15 mL) wasrefluxed for 3 h. The slurry was filtered through celite, and thefiltrate was evaporated to a yellow oil. Purification by flashchromatography on silica gel eluting with 10% ethyl acetate in hexanegave 0.19 g (45%) of the desired aldehyde product as a pale yellow oil.GCMS: m/z=177 [M+H]⁺.

EX-608E) To a 1,2-dichloroethane (4 mL) solution of the aldehyde (0.19g, 1.1 mmol) from EX-608D was added 3-phenoxyaniline (0.20 g, 1.1 mmol),NaB(OAc)₃H (0.30 g, 1.4 mmol) and acetic acid (0.065 mL, 1.1 mmol). Thecloudy solution was stirred at room temperature for 3 h. The reactionmixture was poured into water and extracted with dichloromethane. Theorganic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄)and evaporated to yield 0.32 g (84%) of the desiredN-(3-phenoxyphenyl)[[3-(tetrahydro-2-furanyl)phenyl]methyl]amine productas a yellow oil which was used without further purification. Theformation of the desired product was monitored by TLC.

To a CH₃CN (1 mL) solution of the amine (0.32 g, 0.93 mmol) from EX-608Ewas added 1,1,1-trifluoro-2,3-epoxypropane (0.24 mL, 2.8 mmol) andYb(OTf)₃ (0.115 g, 0.18 mmol). The cloudy solution was stirred in asealed flask at 40° C. for 18 h. The cooled reaction mixture was dilutedwith diethyl ether and washed with water and brine. The organic layerwas dried (MgSO₄) and evaporated to an oil. Purification by flashchromatography on silica gel eluting with 15% ethyl acetate in hexanegave an oil which was dissolved in EtOH, stripped and dried in vacuo togive 0.13 g (30%) of the desired3-[(3-phenoxyphenyl)[[3-(tetrahydro-2-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a colorless oil. Anal. calcd. for C₂₆H₂₆NO₃F₃.0.5 EtOH: C,67.33; H, 6.04; N, 2.94. Found: C, 67.49; H, 6.08; N, 2.91. HRMS calcd.458.1943 [M+H]⁺, found: 458.1937. ¹H NMR (C₆D₆) δ0.45 (d, 1H), 1.43 (m,3H), 1.79 (m, 1H), 1.99 (m, 1H), 3.24 (m, 1H), 3.43 (m, 1H), 3.76 (m,2H), 4.24 (s, 2H), 4.60 (t, 1H), 6.35 (m, 1H), 6.43 (dd, 1H), 6.54 (dd,1H), 6.8 (m, 2H), 6.9-7.0 (m, 7H), 7.15 (d, 1H).

EXAMPLE 609

4-[3-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)aminolphenoxy]phenol

A 1,2-dichloroethane (4 mL) solution ofN-[(4-methoxyphenoxy)phenyl]-3-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1-1,1,1-trifluoro-2-propanol(0.33g, 0.62 mmol) and boron tribromide-methyl sulfide complex (2.5 mL,1.0 M in CH₂Cl₂, 2.5 mmol) was refluxed for 8 h under argon. Thereaction was diluted with Et₂OH and washed with water, 1 N NaOH andsaturated aq. NH₄Cl. The organic layer was dried (MgSO₄) and evaporatedto give a red oil. Purification by flash chromatography on silica geleluting with 30% ethyl acetate in hexane gave an oil which was dissolvedin EtOH, stripped and dried in vacuo to give 0.082 g (25%) of thedesired4-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]phenolproduct as a light red oil. Anal. calcd. for C₂₄H₂NO₄F₇.0.35 EtOH.0.65H₂O: C, 54.21; H, 4.31; N, 2.56; Found: C, 54.20; H, 4.30; N, 2.55; HRMScalcd. 520.1359 [M+H]⁺, found: 520.1325. ¹H NMR (C₆D₆) δ1.96 (d, 1H),3.09 (dd, 1H), 3.43 (dd, 1H), 3.74 (m, 1H), 4.10 (s, 2H), 4.52 (s, 1H),5.09 (tt, 1H), 6.17 (dd, 1H), 6.4 (m, 4H), 6.66 (d, 1H), 6.8-6.9 (m,61H).

EXAMPLE 610

3-(3-phenoxyphenyl)-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-(trifluoromethyl)oxazolidine

A toluene solution (5 mL) of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde(0.45 g, 2.0 mol) andN-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.60 g, 2.0mmol) was refluxed in the presence of molecular sieves and ZnI₂ (˜5 mg)for 18 h under N₂. The reaction mixture was filtered to remove thesieves, and the filtrate was diluted with ethyl acetate. The organiclayer was washed with brine, dried (MgSO₄) and evaporated to give 0.92 g(92%) of the desired3-(3-phenoxyphenyl)-2-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-5-(trifluoromethyl)oxazolidine product as a colorless oil. The formation of the desiredproduct was monitored by the disappearance of the aldehyde peak (δ˜10)in the ¹H NMR spectrum. HRMS calcd. 502.1253 [M+H]⁺, found: 502.1220.

EXAMPLE 611

4-[bis-[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-butanol

EX-611A) The 2-hydroxy-1,1,1-trifluorobutyronitrile (5.0 g, 36 mmol, H.C. Brown et al. J. Org. Chem. 60, 41-46, 1995) was added slowly to astirred suspension of LiAlH₄ (1.7 g, 43.7 mmol) in 8 mL of dry diethylether at 0-5° C. The mixture was stirred at this temperature for 30 min,heated for 45 min, then stirred at room temperature for 2 h. Thereaction mixture was quenched with 5.5 mL of aq. sat. Na₂SO₄ and stirredfor 1 h. The mixture was filtered through a celite pad, and the pad waswashed with ether. The filtrate and ether washings were collected andevaporated to give 4.2 g (82%) of crude4-amino-2-hydroxy-1,1,1-trifluorobutane product as a brownish solid.HRMS calcd. for C₄H₈NOF₃: 144.0636 [M+H]⁺, found 144.0622.

The 4-amino-2-hydroxy-1,1,1-trifluorobutane (0.57 g, 4 mmol) fromEX-611A and 3-(trifluoromethoxy)benzyl bromide (2.04 g, 8.0 mmol) weredissolved in 10 mL of anhydrous ethanol. Potassium carbonate (1.10 g, 8mmol) was added, and the mixture was heated to reflux for 3 days, atwhich time HPLC analysis indicated the formation of product, asconfirmed by MS. The reaction mixture was quenched with water andextracted with ether. The ether layer was washed with water and brine,then dried over MgSO₄, and evaporated to give crude product, which waspurified by flash column chromatography on silica gel eluting with1:10:0.01 to 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give0.53 (27%) of the desired4-[bis-[[3-(tri-fluoromethoxy)phenyl]methyl]amino]1,1,1-trifluoro-2-butanolproduct as a yellow oil. ¹H NMR (CDCl₃) δ7.37 (t, 2H), 7.23 (d, 2H),7.14 (d, 4H), 5.68 (bs, 1H), 3.98 (m, 1H), 3.76 (d, 2H), 3.45 (d, 2H),2.78 (dd, 2H), 1.90 (m, 1H), 1.83 (m, 1H). ¹⁹F NMR (CDCl₃) δ−58.27 (s,6F), −80.54 (d, 3F). HRMS calcd. for C₂₀H₁₈NO₃F₉: 492.1221 [M+H]⁺,found: 492.1184.

EXAMPLE 612

N,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamide

EX-612A) Methyl 3-(bromomethyl)benzoate (7.2 g, 0.031 mol) was addeddropwise to a solution of 3-phenoxyaniline (20.5 g, 0.11 mol) in 160 mLof cyclohexane. The reaction mixture was refluxed overnight then cooledto room temperature and diluted with water and methylene chloride. Thelayers were separated, and the aqueous layer was extracted withmethylene chloride. The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated in vacuo to give a dark oil. Thecrude product was purified by reverse phase HPLC eluting with 20% to 90%acetonitrile in water to afford 6.2 g (59%) of the desired methyl3-[[(3-phenoxyphenyl)amino]methyl]benzoate product as a yellow oil. ESMSm/z=334 [M+H]⁺.

EX-612B) To a mixture of methyl3-[[(3-phenoxyphenyl)amino]methyl]benzoate (6.2 g, 0.019 mol) fromEX-612A and 1,1,1-trifluoro-2,3-epoxypropane (8.58 g, 0.077 mol) in 12mL of acetonitrile was added ytterbium (III) trifluoromethanesulfonate(1.2 g, 0.0019 mol). The resulting mixture was heated at 50° C. in asealed glass tube for 18 h. The reaction mixture was cooled to roomtemperature, then diluted with water and methylene chloride. The aqueouslayer was extracted with methylene chloride. The organic layers werecombined, dried over MgSO₄, and concentrated in vacuo. The crude productwas purified by column chromatography on silica gel eluting with 1:9ethyl acetate in hexane to afford 8.0 g (96%) of the desired methyl3-[[(3-phenoxy-phenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoateproduct as a yellow oil. Anal. calcd. for C₂₄H₂₂F₃NO₄.1.4 H₂O: C, 61.25;H, 5.31; N, 2.98. found: C, 61.52; H, 5.06; N, 2.89. HRMS calcd.:446.1579 [M+H]⁺, found: 446.1596. ¹H NMR (CDCl₃) δ7.28 (m, 4H), 7.14 (t,1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd,1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d,1H), 3.48 (m, 1H), 2.51 (s, 1H). ¹⁹F NMR (CDCl₃) δ−79.0 (d, 3F).

To a solution of N,N-dimethylamine hydrochloride (525 mg, 0.0064 mol) in3.0 mL of toluene at −40° C. was added dropwise a 2.0 M solution oftrimethylaluminum in toluene (3.2 mL, 0.0064 mol) over 15 min. Thereaction mixture was warmed to room temperature and stirred for 2 h. Toa solution of methyl3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate(209 mg, 0.00047 mol) from EX-612B in 2.5 mL of toluene at −10° C. wasslowly added the (N,N-dimethylamino)chloromethylaluminum reagent (850μL, 0.00085 mol). The reaction mixture was warmed to room temperaturethen heated at 40° C. overnight. The reaction mixture was cooled to roomtemperature, then diluted with ethyl acetate and quenched with 10%aqueous potassium hydrogen phosphate. The organic layer was dried overMgSO₄ and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel eluting with 2:3 ethyl acetate inhexane to afford 195 mg (91%) of the desiredN,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]-benzamideproduct as a pale yellow solid. Anal. calcd. for C₂₅H₂₅F₃N₂O₃.0.5 H₂O:C, 64.23; H, 5.61; N, 5.99. Found: C, 64.49; H, 5.77; N, 5.85. HRMScalcd. 459.1896 [M+H]⁺, found: 458.1887. ¹H NMR (C₆D₆) δ7.01-6.95 (m,3H), 6.92-6.87 (m, 5H), 6.79 (t, 1H), 6.46 (s, 1H), 6.37 (t, 2H), 4.91(bs, 1H), 4.26 (s, 2H), 4.10 (bq, 1H). 3.84 (dd, 1H), 3.38 (dd, 1H),2.53 (bs, 3H), 2.14 (bs, 3H). ¹⁹F NMR (C₆D₆) δ−78.69 (d, 3F).

Additional examples of N,N-dialkyl-andN,N-cycloalkyl-3-[[(3-phenoxy-phenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamidescan be prepared by one skilled in the art using similar methods, asshown in Example Table 36.

Example Table 36. N,N-dialkyl- and N,N-cycloalkyl-3-[[(3-phenoxy-phenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamides.

Ex. Calculated Observed Mass No. R_(SUB1) R_(SUB2) Mass [M + H]⁺ [M +H]⁺ 613 methyl ethyl 473.2052 473.2055 614 methyl propyl 487.2209487.2193 615 methyl butyl 501.2365 501.2357 616 —(CH₂CH₂CH₂CH₂)—485.2052 485.2057

EXAMPLE 617

α,α-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol

To a solution of methyl3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxy-propyl)amino]methyl]benzoate(218 mg, 0.00049 mol) in 0.7 mL of tetrahydrofuran at 0° C. was slowlyadded a 3.0 M solution of methylmagnesium chloride in THF (650 μL,0.0020 mol). The reaction mixture was warmed to room temperature,stirred for 2 h, then diluted with diethyl ether and quenched withsaturated aqueous ammonium chloride. The aqueous layer was extractedwith dichloromethane, and the combined organic layers were dried overMgSO₄ and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel eluting with 1:4 ethylacetate:hexane to afford 174 mg (80%) of the desiredα,α-dimethyl-3-[[(3-phenoxy-phenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanolproduct as a slightly yellow oil. Anal. calcd. for C₂₅H₂₆F₃NO₃.0.5 H₂O:C, 66.07; H, 5.99; N, 3.08. found: C, 66.12; H, 6.34; N, 2.92. HRMScalcd. 466.1943 [M+H]⁺, found: 446.1938. ¹H NMR (CDCl₃) δ7.34 (s, 1H),7.32-7.21 (m, 4H), 7.13 (t, 1H), 7.09-7.01 (m, 2H), 6.94 (d, 2H), 6.50(d, 1H), 6.41 (s, 1H), 6.37 (d, 1H), 4.61 (s, 2H), 4.27 (bt, 1H), 3.81(appd, 1H), 3.53 (dd, 1H), 3.33 (bs, 1H), 1.96 (bs, 1H), 1.51 (s, 6H).¹⁹F NMR (CDCl₃) δ−78.88 (d, 3F).

EXAMPLE 618

3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol

To a solution of methyl3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxy-propyl)amino]methyl]benzoate(197 mg, 0.00044 mol) in 2.0 mL of dichloromethane at −40° C. was slowlyadded a 1.0 M solution of lithium aluminum hydride in THF (1.1 mL,0.0011 mol). The reaction mixture was stirred at −40° C. for 1 h, thendiluted with ethyl acetate and quenched with water. The organic layerwas dried over MgSO₄ and concentrated in vacuo. The crude material wasdetermined to contain a significant amount of unreacted startingmaterial by HPLC at this stage. The crude material was resubjected tothe reaction conditions using 2 mL of anhydrous tetrahydrofuran and 1.0M lithium aluminum hydride (1.3 mL, 0.0013 mol) at −40° C. for 1 h, thendiluted with ethyl acetate and quenched with water. The aqueous layerwas extracted with ethyl acetate, and the combined organic layers weredried over MgSO₄ and concentrated in vacuo. The crude product waspurified by column chromatography on silica gel eluting with 2:3 ethylacetate:hexane to afford 99 mg (54%) of the desired3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanolproduct as a white solid. Anal. calcd. for C₂₃H₂₂F₃NO₃: C, 66.18; H,5.31; N, 3.36. Found: C, 65.98; H, 5.39; N, 3.22. HRMS calcd. 418.1630[M+H]⁺, found: 418.1636. ¹H NMR (C₆D₆) δ7.08-6.92 (m, 8H), 6.89-6.80 (m,2H), 6.56 (s, 1H), 6.46 (d, 1H), 6.38 (d, 1H), 4.26 (s, 2H), 4.21 (d,2H), 3.77 (appq, 1H), 3.52 (d, 1H), 1.92 (bs, 1H), 0.96 (bs, 1H). ¹⁹FNMR (C₆D₆) δ−78.91 (d, 3F).

EXAMPLE 619

α,α-bis(trifltuoromethyl)-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol

To a solution of methyl3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)-amino]methyl]benzoate(331 mg, 0.00074 mol) and trimethyl(trifluoromethyl)silane (423 mg,0.0030 mol) in 3.0 mL of toluene at room temperature was added a 1.0 Msolution of tetrabutylammonium fluoride in THF (150 μL, 0.00015 mol)which had been dried over molecular sieves. The reaction mixture washeated at 40° C. for 18 h. HPLC analysis indicated incomplete reactiontherefore additional trimethyl(trifluoro-methyl)silane (440 μL, 0.0030mol) and tetrabutylammonium fluoride (150 μL, 0.00015 mol) were added,and the reaction mixture was heated to 50° C. in a sealed glass vial.After 2 h, HPLC analysis indicated no ester starting material remained.The reaction mixture was quenched with water and extracted withdichloromethane. The organic layer was dried over MgSO₄ and concentratedin vacuo. The crude product was purified by column chromatography onsilica gel eluting with 1:9 ethyl acetate:hexane to afford 26 mg (6%) ofthe desiredα,α-bis(trifluoromethyl)-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol product as a yellow-brown oil. HRMS calcd.for C₂₅H₂₀F₉NO₃: 554.1378 [M+H]⁺, found: 554.1385. ¹H NMR (CDCl₃) δ7.69(dd, 1H), 7.57 (apps, 1H), 7.52 (dd, 1H), 7.37 (t, 1H), 7.29-7.23 (m,2H), 7.14 (t, 1H), 7.05 (t, 1H), 6.92 (d, 2H), 6.47 (d, 1H), 6.38 (d,1H), 6.37 (s, 1H), 4.66 (s, 2H), 4.29 (m, 1H), 3.82 (d, 1H), 3.54 (dd,1H). ¹⁹F NMR (CDCl₃) δ−75.81 (dq, 6F), −79.18 (d, 3F).

EXAMPLE 620

1-[3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)-amino]methyl]phenyl]-1-propanone

EX-620A) To a slurry of methyl3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate(1.03 g, 0.0023 mol) and N,O-dimethyl-hydroxylamine hydrochloride (386mg, 0.0040 mol) in 4.6 mL of tetrahydrofuran at −15° C. was added a 2.0M solution of isopropylmagnesium chloride in THF (4.6 mL, 0.0092 mol)over 15 min. The reaction was stirred for 1 h at −15° C. then quenchedwith 20% aqueous ammonium chloride and extracted with ethyl acetate. Theorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Thecrude product was purified by column chromatography on silica geleluting with 1:1 ethyl acetate:hexane to afford 0.72 g (66%) of thedesiredN-methoxy-N-methyl-3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamideproduct as an off-white solid. HRMS calcd. for C₂₅H₂₅N₂O₄F₃: 475.1845[M+H]⁺, found: 475.1840.

To a solution of N-methoxy-N-methylbenzamide (208 mg, 0.00044 mol) fromEX-620A in 2.2 mL of tetrahydrofuran at −15° C. was added a 1.0 Msolution of ethyl-magnesium bromide in THF (950 μL, 0.0095 mol). Thereaction mixture was slowly warmed to room temperature then leftstirring overnight. HPLC analysis indicated unreacted starting materialwas still present so additional ethylmagnesium bromide (440 μL, 0.0044mol) was added. After 3 h at room temperature, the reaction mixture wasdiluted with diethyl ether and quenched with 1 N HCl. The aqueous layerwas extracted with diethyl ether and the combined organic layers weredried over MgSO₄ and concentrated in vacuo. The crude product waspurified by column chromatography on silica gel eluting with 1:4 ethylacetate in hexane to afford 121 mg (62%) of the desired1-[3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)-amino]methyl]phenyl]-1-propanoneproduct as a pale yellow oil. HRMS calcd. for C₂₅R₂₄F₃NO₃: 444.1787[M+H]⁺, found: 444.1786. ¹H NMR (CDCl₃) δ7.83 (d, 1H), 7.78 (s, 1H),7.38 (appq, 2H), 7.27 (appq, 2H), 7.15 (t, 1H), 7.06 (t, 1H), 6.94 (d,2H), 6.48 (d, 1H), 6.39 (d, 1H), 6.37 (s, 1H), 4.68 (s, 2H), 4.35 (m,1H), 3.88 (dd, 1H), 3.56 (dd, 1H), 2.95 (q, 2H), 1.20 (t, 3H). ¹⁹F NMR(CDCl₃) δ−79.17 (d, 3F).

Additional examples of1-[3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxy-propyl)amino]methyl]-phenyl]-1-alkanonescan be prepared by one skilled in the art using similar methods, asshown in Example Table 37.

Example Table 37. 1-[3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxy-propyl)amino]methyl]-phenyl]-1-alkanones.

Ex. Calculated Mass Observed Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 621isobutyl 472.2130 472.2100

EXAMPLE 622

3-[[4-(phenylethynyl)-(3-(trifluoromethyl)phenyl][[3-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

The3-[(3-(trifluoromethyl)-4-bromophenyl)[[3-(1,1,1-trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol(0.33 g, 0.648 mmol) and tributylstannylphenyl-acetylene (0.278 g, 0.712mmol) were added to degassed 1,2-dichloroethane. The resulting mixturewas stirred at room temperature for 10 min, then Pd(PPh₃)₂Cl₂ (0.032 g.0.045 mmol) was added. The mixture was stirred 18 h at room temperature.More tributyl-stannylphenylacetylene (0.278 g, 0.712 mmol) andPd(PPh₃)₂Cl₂ (0.032 g, 0.045 mmol) were added. The solution was refluxedfor 72 h. The reaction mixture was diluted with diethyl ether andstirred in 10% aq. KF for 18 h. The organic layer was collected, driedover MgSO₄ and concentrated. The crude product was purified by flashcolumn chromatography on silica gel eluting with 1:4 ethyl acetate inhexane to give 0.102 g (30%) of the desired3-[[4-(phenylethynyl)-(3-(trifluoromethyl)phenyl][[3-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a pure yellow oil. Anal calcd. For C₂₆H₁₈NOF₉: C, 58.76; H,3.41; N, 2.64. Found: C, 58.72; H, 3.67; N, 2.47. HRMS calcd. 532.1322[M+H]⁺, found: 532.1304. ¹H NMR (CDCl₃) δ7.52 (m, 4H), 7.38 (dd, 2H),7.32 (dd, 2H), 7.24 (dd, 1H), 7.00 (s, 1H), 6.78 (dd, 1H), 4.80 (s, 2H),4.36 (m, 1H), 3.92 (d, 1H), 3.65 (m, 1H), 2.60 (d. 1H). ¹⁹F NMR (CDCl₃)δ−63.5 (s, 6F), −79.38 (d. 3F).

Additional examples of3-[[4-(heteroaryl)-(3-(trifluoromethyl)phenyl][[3-(tri-fluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolscan be prepared by one skilled in the art using similar methods, asshown in Example Table 38.

Example Table 38. 3-[[4-(heteroaryl)-(3-(trifluoromethyl)phenyl]-[[3-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Mass Observed Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 6232-thienyl 514.0887 514.0912 624 2-furanyl 498.1037 498.1116

EXAMPLE 625

3-[4-bromo-3-(trifluoromethyl)phenyl[[3-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-625A) The α,α,α-trifluoro-m-tolualdehyde (3.63 g, 0.021 mol) wasadded neat to 4-bromo-3-trifluoromethylaniline (5.0 g, 0.021 mol).Dichloroethane (50 mL) was added followed by sodiumtriacetoxyborohydride (4.85 g, 0.023 mol) and acetic acid (1.42 g, 0.024mol). The resulting mixture was stirred at room temperature for 18 h,then diluted with methylene chloride, quenched with sodium bicarbonateand extracted with methylene chloride. The organic layers were combinedand dried over MgSO₄ and concentrated to give 6.97 g of the desired3-[4-bromo-3-(trifluoromethyl)-phenyl[[3-(trifluoromethyl)phenyl]methyl]amineproduct as a yellow oil, which was carried forward without purification.ESMS m/z=397 [M+H]⁺.

The amine product (6.97 g, 0.018 mol) from EX-625A was mixed with1,1,1-trifluoro-2,3-epoxypropane (3.92 g, 0.035 mol) in a pressurizedvial. A suspension of ytterbium triflate (1.08 g, 0.002 mol) in 2.0 mLof acetonitrile was added. The resulting mixture was stirred at roomtemperature for 18 h, then quenched with water and extracted with ethylacetate. The crude product was purified by flash column chromatographyon silica gel eluting with 1:4 ethyl acetate in hexane to give 1.04 g(11%) of the desired3-[4-bromo-3-(trifluoromethyl)phenyl[[3-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a pure yellow oil. Anal calcd. for C₁₈H₁₃NOF₉Br: C, 42.38; H,2.57; N, 2.75. Found: C, 42.16; H, 2.71; N, 2.71. HRMS calcd. 510.0115[M+H]⁺, found: 510.0139. ¹H NMR (C₆D₆) δ7.40 (d, 2H), 7.20 (d, 1H), 7.10(m, 2H), 6.98 (d, 1H), 6.18 (dd, 1H), 4.00 (s, 2H), 3.63 (m, 1H), 3.40(d. 1H), 3.02 (m, 1H), 1.80 (d, 1H). ¹⁹F NMR (C₆D₆) δ−62.35 (s, 3F),−65.00 (s, 3F), −78.58 (d, 3F).

EXAMPLE 626

3-[[1-methyl-3-[3-(trifluoromethoxy)phenyl]propyl](3-phenoxyphenyl)amino]-1,1,1-trifluoro-2-propanol

EX-626A) Tetrabutylammonium iodide (0.4 g, 0.05 mol) was added to awell-stirred biphasic mixture of 12 mL of 50% NaOH and 20 mL ofmethylene chloride under a nitrogen atmosphere. A solution of3-trifluoromethoxybenzaldehyde (4.0 g, 0.021 mol) and diethyl(2-oxopropyl)phosphonate (4.08 g, 0.021 mol) in 4.0 mL of methylenechloride was added dropwise to the stirred solution. The resultingmixture was stirred at room temperature for 15 min, then quenched withwater and extracted with hexane. The hexane layer was dried over MgSO₄.The crude product was purified by flash column chromatography on silicagel eluting with 1:10 ethyl acetate in hexane to give 2.6 g (54%) of thedesired 4-[3-(trifluoromethoxy)phenyl]-3-buten-2-one product as a yellowoil. ¹H NMR (CDCl₃) δ7.43 (m, 4H), 7.20 (d, 1H), 6.65 (d, 2H), 2.29 (s,3H). ¹⁹F NMR (CDCl₃) δ−62.05 (s, 3F).

EX-626B) The product (1.0 g, 0.0004 mol) from EX-626A was dissolved in25 mL of ethanol and the reaction vessel was charged with nitrogen.Palladium (10% on carbon) (0.30 g, 30%) was added to the solution. Themixture was hydrogenated for 3 h at room temperature. The palladium wasfiltered off through a celite pad. The filtrate was concentrated to give0.79 g (85%) of the desired 4-[3-(trifluoromethoxy)phenyl]-butan-2-oneas a yellow oil. ESMS m/z=232 [M+H]⁺.

EX-626C) In a flask equipped with a stir bar and molecular sieves, asolution of 3-phenoxyaniline (1.1 g, 0.0059 mol) in 15 mL of cyclohexanewas prepared under nitrogen. A solution of the ketone (1.3 g, 0.006 mol)product from EX-626B dissolved in 5 mL of cyclohexane was added. Themixture was refluxed for 18 h, filtered and concentrated to give thedesired imine product as a dark yellow oil. ESMS m/z=400 [M+H]⁺.

EX-626D) The imine product (1.3 g, 0.003 mol) from EX-626C was stirredwith 5 mL of methanol at 0° C. Sodium borohydride (0.23 g, 0.005 mol)was added to the mixture, and the mixture was stirred at roomtemperature for 18 h. The mixture was acidified with 4 mL of 3% HCl andextracted with diethyl ether. The ether layers were combined, dried overMgSO₄ and concentrated to give 1.07 g (81%) of the desired3-[1-methyl-3-[3-(trifluoromethoxy)phenyl]propyl](3-phenoxyphenyl)amineproduct as an orange oil. ESMS m/z=402 [M+H]⁺.

The3-[1-methyl-3-[3-(trifluoromethoxy)phenyl]propyl](3-phenoxyphenyl)amine(1.0 g, 0.002 mol) product from EX-626D and1,1,1-trifluoro-2,3-epoxypropane (0.56 g, 0.005 mol) were heated at 90°C. for 18 h. Excess epoxide was evaporated. The crude product waspurified by flash column chromatography on silica gel eluting with 1:13ethyl acetate in hexane to give 0.16 g (13%) of the desired3-[[1-methyl-3-[3-(trifluoro-methoxy)phenyl]propyl](3-phenoxyphenyl)amino]-1,1,1-trifluoro-2propanolproduct as a yellow oil. Anal calcd. for C₂₆H₂₅NO₃F₆: C, 60.82; H, 4.91;N, 2.72. Found: C, 60.63; H, 4.89; N, 2.70. HRMS calcd. 514.1816 [M+H]⁺,found: 514.1789. ¹H NMR (C₆D₆) δ7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m,3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46(dd, 1H), 6.38 (dd, 1H), 6.35 (t,H), 4.18 (m, 1H), 3.78 (m, 1H), 3.52 (dd, 1H), 3.28 (m, 1H), 2.76 (s,1H), 2.53 (m, 2H), 1.92 (m, 1H), 1.63 (m, 1H), 1.24 (m, 3H). ¹⁹F NMR(CDCl₃) δ−56.84 (s, 3F), −79.0 (s, 3F).

EXAMPLE 627

3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]methoxymethylbenzene

EX-627A) A suspension of N-bromosuccinimide (17.6 g, 0.099 mol) incarbon tetra-chloride was added to a stirring solution of m-xylene incarbon tetrachloride. Then 2,2-azobisisobutyronitrile catalyst (0.71 g,0.004 mol) was added. The resulting mixture was refluxed for 2 h, thenquenched with 50 mL of water. The organic layer was collected, washedwith water followed by brine, dried over MgSO₄ and concentrated to give2.0 g (16%) of the desired crude 1,3-dibromoxylene product. ESMS m/z=264[M+H]⁺.

EX-627B) The 1,3-dibromoxylene (2.0 g, 0.0076 mol) from EX-627A andsodium methoxide (2.45 g, 0.045 mol) were mixed in 25 mL of MeOH. Theresulting mixture was stirred at room temperature for 18 h,concentrated, dissolved in methylene chloride and washed with water. Theorganic layer was further washed with brine and dried over MgSO₄ andconcentrated to give 0.912 g (72%) of the desired1,3-di-(methoxy-methyl)benzene product as a yellow oil. ESMS m/z=166[M+H]⁺.

EX-627C) The diether product (0.90 g, 0.0054 mol) from EX-627B wasstirred in a mixture of 10:1 methylene chloride:water. To this was added2,3-dichloro-5,6-dicyano-benzoquinone (1.84 g, 0.0081 mol). Theresulting biphasic mixture was stirred at room temperature for 72 h. Themixture was then washed with saturated sodium bicarbonate followed bybrine, dried over MgSO₄ and concentrated. The crude product was purifiedby flash column chromatography on silica eluting with 1:4 ethylacetate:hexane to give 0.430 g (53%) of the desired3-(methoxymethyl)benzaldehyde product as a pink oil. ¹H NMR (CDCl₃)δ10.00 (s, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.63 (d, 1H), 7.51 (t, 1H),4.58 (s, 2H), 3.40 (s, 3H).

EX-627D) The 3-(methoxymethyl)benzaldehyde (0.430 g, 2.87 mmol) fromEX-627C was added to a stirring solution of 3-phenoxyaniline (0.530 g,2.87 mmol) in 5 mL of dichloromethane. Then sodium triacetoxyborohydride(0.670 g, 3.16 mmol) was added followed by acetic acid (0.196 g, 3.27mmol). The resulting mixture was stirred at room temperature 18 h, thendiluted in methylene chloride and quenched with sodium bicarbonate. Theorganic layer was washed with brine, dried over MgSO₄ and concentratedto give 0.870 g (95%) of the desiredN-3-(phenoxyphenyl)-[[3-(methoxy-methyl)phenyl]methyl]amine product as apink oil. ESMS m/z=320 [M+H]⁺.

The N-3-(phenoxyphenyl)[[3-(methoxymethyl)phenyl]methyl]amine product(0.87 g, 0.003 mol) from EX-627D was mixed with1,1,1-trifluoro-2,3-epoxypropane (0.61 g, 0.005 mol) in a pressurizedvial. A suspension of ytterbium triflate (0.16 g, 0.272 mmol) in 0.5 mLof acetonitrile was added. The resulting mixture was stirred at roomtemperature for 18 h, then quenched with water and extracted with ethylacetate. The crude product was purified by flash column chromatographyon silica gel eluting with 1:4 ethyl acetate:hexane to give 0.35 g (30%)of the desired3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]methoxymethylbenzeneproduct as a pure yellow oil. Anal calcd. for C₂₄H₂₄NO₃F₃.0.5 H₂O: C,65.18; H, 5.61; N, 3.17. Found: C, 65.19; H, 5.36; N, 3.13. HRMS calcd.432.1786 [M+H]⁺, found: 432.1803. ¹H NMR (C₆D₆) δ6.82 (m, 7H), 6.60 (dd,1H), 6.42 (dd, 1H), 6.38 (s, 1H), 6.18 (dd, 1H), 4.00 (s, 2H), 3.63 (m,1H), 3.40 (d, 1H), 3.02 (m, 1H), 1.80 (d, 1H). ¹⁹F NMR (C₆D₆) δ−78.55(s, 3F).

EXAMPLE 628

3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-628A) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (50 g,0.24 mol) and N-bromosuccinimide (42.75 g, 0.24 mol) in 100 mL of carbontetrachloride under nitrogen was added 2,2′-azobisisobutyronitrile (0.71g, 0.004 mol). The resultant mixture was refluxed for 2 h then cooled toroom temperature and quenched with 300 mL of water. The organic layerwas collected, washed with water and brine, dried over MgSO₄, andconcentrated in vacuo to give 66.0 g (96%) of the desired crude3-(1,1,2,2-tetrafluoroethoxy)bromomethylbenzene product as a yellow oil.¹H NMR indicates that this oil is a mixture of products: 7%dibrominated, 67% monobrominated, and 20% starting material. The crudeproduct was used without further purification. ESMS m/z=287 [M+H]⁺.

EX-628B) The crude product (56 g, 0.14 mol) from EX-628A in 200 mL ofcyclohexane was added dropwise under nitrogen to a solution of3-phenoxyaniline (89 g, 0.480 mol) in 500 mL of cyclohexane. Thereaction mixture was refluxed overnight, then cooled to room temperatureand diluted with water and diethyl ether. The layers were separated, andthe aqueous layer was extracted with diethyl ether. The combined organiclayers were dried over MgSO₄ and concentrated in vacuo to give a darkoil. The crude product was purified by column chromatography on silicagel eluting with 1:4 ethyl acetate in hexane to afford 44.96% g (83%) ofthe desiredN-3-(phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amineproduct as a yellow oil. ESMS m/z=392 [M+H]⁺.

To a mixture of the amine product (15.0 g, 0.038 mol) from EX-628B and1,1,1-tri-fluoro-2,3-epoxypropane (8.58 g, 0.077 mol) was added asuspension of ytterbium (III) trifluoromethanesulfonate (2.37 g, 0.0031mol) in 15 mL of acetonitrile. The resulting mixture was heated at 50°C. in a sealed glass vial for 1.5 h. The reaction mixture was cooled toroom temperature then diluted with water and ethyl acetate andextracted. The organic layers were combined, dried over MgSO₄, andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel eluting with 1:4 ethyl acetate in hexane toafford 12.03 g (62%) of the desired3[(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a yellow oil. Anal. calcd. for C₂₄H₂₀F₇NO₃: C, 57.26; H,4.00; N, 2.78. Found: C, 56.96; H, 4.35; N, 2.69. HRMS calcd. 504.1410[M+H]⁺, found: 504.1431. ¹H NMR (CDCl₃) δ7.28 (m, 4H), 7.14 (t, 1H),7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H),6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H),3.48 (m, 1H), 2.51 (s, 1H). ¹⁹F NMR (CDCl₃) δ−79.0 (s, 3F), −88.21 (d,2F), −137.05 (dd, 2F).

EXAMPLE 629

3-[[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-629A) 3-Aminophenol (5 g, 46 mmol), 1-bromo-2,4-difluorobenzene (10g, 50 mmol) and Cs₂CO₃ (16 g, 50 mmol) were mixed in 25 mL ofdimethylformamide. Solid (CuOTf)₂C₆H₆ (100 mg) was added, and themixture was stirred under nitrogen at 85° C. for 22 h, at which timeHPLC analysis indicated that the reaction had gone to completion andformed two products. The DMF was removed under reduced pressure. Theresidue was diluted with ether and filtered through a celite pad. Thepad was washed with ether and a small amount of water. The mixture wasextracted with ether several times. The combined ether layers werewashed with water and brine, then dried over MgSO₄. The dried organiclayer was evaporated to give 10.2 g (80%) of the desired product, whichconsisted of a 11:1 ratio of 3-(2-bromo-5-fluorophenoxy)-aniline and3-(4-bromo-3-fluorophenoxy)aniline. The crude product was purified byflash column chromatography on silica gel eluting with 1:7:0.01 of ethylacetate:hexane:ammonium hydroxide to give 8.8 g (68%) of the desiredproduct as a yellow oil, which was a 25:1 ratio of3-(2-bromo-5-fluorophenoxy)aniline and3-(4-bromo-3-fluorophenoxy)aniline. HRMS calcd. for C₁₂H₉NOFBr: 281.9930[M+H]⁺, found: 281.9950.

EX-629B) The crude 3-(2-bromo-5-fluorophenoxy)aniline (1.39 g, 4.95mmol) product from EX-629A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde(1.0 g, 4.5 mmol) were dissolved in 15 mL of dichloroethane and aceticacid (0.30 mL, 5.4 mmol), then solid NaBH(OAc)₃ (1.26 g, 5.9 mmol) wasadded. The mixture was stirred at room temperature for 1 h, thenquenched with water and extracted with ether. The ether layer was washedwith water and brine, then dried over MgSO₄, and evaporated to give 2.1g (97%) of crude product, which was purified by flash columnchromatography on silica gel eluting with 1:7:0.01 of ethylacetate:hexane:ammonium hydroxide to give 2.0 g (91%) of the desired3-[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amineproduct, as a light yellow oil, >90% pure by HPLC analysis. HRMS calcd.for C₂₁H₁₅NO₂BrF₅: 488.0285 [M+H]⁺, found: 488.0269.

The 3-[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amine (0.97 g, 2.0 mmol) product from EX-629B and1,1,1-trifluoro-2,3-epoxypropane (0.45 g, 4.0 mmol) were dissolved in1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.12g, 0.2 mmol) was added, and the stirred solution was warmed to 40° C.for 1 h, at which time HPLC analysis indicated that no secondary aminestarting material remained. The reaction was quenched with water andextracted with ether. The ether layer was washed with water and brine,then dried over MgSO₄. The crude product was purified by flash columnchromatography on silica gel eluting with 1:7:0.01 of ethylacetate:hexane:ammonium hydroxide to give 0.83 g (69%) of the desired3-[[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a clear colorless oil, >95% pure by HPLC analysis. ¹H NMR(CDCl₃) δ7.50 (dd, 1H), 7.30 (t, 1H), 7.18 (t, 1H), 7.07 (t. 2H). 6.99(s, 1H), 6.70 (dt, 1H), 6.56 (dd, 1H), 6.52 (dd, 1H), 6.38 (dd, 1H),6.32 (m, 1H), 5.87 (tt, 1H), 4.65 (d, 2H), 4.33 (m, 1H), 3.85 (dd, 1H),3.56 (dd, 1H), 2.48 (bs, 1H). NOE difference spectra confirmed that theisolated material was the indicatedN-]3-(2-bromo-5-fluorophenoxy)phenyl]-3-aminopropanol product. ¹⁹F NMR(CDCl₃) δ−79.24 (d, 3F), −88.57 (m, 2F), −112.04 (q, 1H), −137.16 (dt,2F). Anal. calcd. for C₂₄H₁₈NO₃BrF₈: C, 48.02: H, 3.02; N, 2.33. Found:C, 48.48; H, 3.18; N, 2.33. HRMS calcd. 600.0420 [M+H]⁺, found:600.0415.

EXAMPLE 630

3-[[3-(-5-bromo-2-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-630A) 3-Aminophenol (5 g, 46 mmol), 1-bromo-3,4-difluorobenzene (10g, 50 mmol) and Cs₂CO₃ (16 g, 50 mmol were mixed in 25 mL of DMF. Solid(CuOTf)₂C₆H₆ (100 mg) was added, and the mixture was stirred undernitrogen at 85° C. for 22 h, at which time HPLC analysis indicated thatthe reaction had gone to completion and formed two products. The DMF wasremoved under reduced pressure. The residue was diluted with ether andfiltered through a celite pad. The pad was washed with ether and a smallamount of water. The mixture was extracted with ether several times. Thecombined ether layers were washed with water and brine, then dried overMgSO₄. The dried organic layer was evaporated to give 7.5 g (58%) of thedesired products, which comprised a 10:1 ratio of3-(5-bromo-2-fluorophenoxy)aniline and 3-(4-bromo-2-fluorophenoxy)aniline. The crude product was purified by flash column chromatographyon silica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammoniumhydroxide to give 4.5 g (35%) of the desired products as a yellow oil,which were a 20:1 ratio of 3-(5-bromo-2-fluorophenoxy)aniline and3-(4-bromo-2-fluorophenoxy)-aniline. HRMS calcd. for C₁₂H₉NOFBr:281.9930 [M+H]⁺, found 281.9951.

EX-630B) The crude 3-(5-bromo-2-fluorophenoxy)aniline (1.39 g, 4.95mmol) product from EX-630A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde(1.0 g, 4.5 mmol) were dissolved in 15 mL of dichloroethane and aceticacid (0.30 mL, 5.4 mmol), then solid NaBH(OAc)₃ (1.26 g, 5.9 mmol) wasadded. The mixture was stirred at room temperature for 1 h, thenquenched with water and extracted with ether. The ether layer was washedwith water and brine, then dried over MgSO₄, and evaporated to give 2.1g (97%) of crude product, which was purified by flash columnchromatography on silica gel eluting with 1:7 ethyl acetate:hexane togive 2.0 g (91%) of the desired3-[3-(5-bromo-2-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amineproduct, as a yellow oil, >95% pure by HPLC analysis. Anal. calcd. forC₂₁H₁₅NO₂BrF₂: C, 51.66; H, 3.10; N, 2.87. Found: C, 51.90; H, 3.08; N,2.86. HRMS calcd. 488.0284 [M+H]⁺. found 488.0281.

The amine (1.1 g, 2.26 mmol) product from EX-630B and1,1,1-trifluoro-2,3-epoxypropane (0.38 g, 3.39 mmol) were dissolved in 1mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.14 g,0.23 mmol) was added, and the stirred solution was warmed to 40° C. for1 h, at which time HPLC analysis indicated that no secondary aminestarting material remained. The reaction was quenched with water andextracted with ether. The ether layer was washed with water and brine,then dried over MgSO₄. The crude product was purified by flash columnchromatography on silica gel eluting with 1:7 ethyl acetate:hexane togive 0.5 g (37%) of the desired3-[[3-(5-bromo-2-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-tri-fluoro-2-propanolproduct as a yellow oil, >95% pure by HPLC analysis. ¹H NMR (CDCl₃)δ7.50 (t, 1H), 7.20 (dd, 1H), 7.17 (dd, 1H). 7.17 (dd, 1H), 7.09 (t,2H), 7.00 (dd, 2H), 6.52 (dd, 1H), 6.38 (dd, 1H), 6.37 (s, 1H), 5.87(tt, 1H), 4.64 (s, 2H), 4.33 (m, 1H), 3.85 (dd, 1H), 3.56 (dd, 1H). ¹⁹FNMR (CDCl₃) δ−79.20 (d, 3F), −88.55 (m, 2F), −113.04 (m, 1H), −137.05(dt, 2F). NOE difference and pcosy spectra confirmed that the isolatedmaterial was the indicatedN-[3-(5-bromo-2-fluorophenoxy)phenyl]-3-aminopropanol product. Anal.calcd. for C₂₄H₁₈NO₃BrF₈: C, 48.02; H, 3.02; N, 2.33. Found: C, 48.07;H, 3.14; N, 2.31. HRMS calcd. 600.0420 [M+H]⁺, found: 600.0404.

EXAMPLE 631

3-[(3-phenoxyphenyl)[[4-(N,N-diethylamino)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-631A) The 3-phenoxyaniline aniline (0.74 g, 4.0 mmol) and4-(N,N-diethylamino)benzaldehyde (0.59 g, 3.3 mmol) were dissolved in 10mL of dichloroethane and acetic acid (0.22 mL, 4.0 mmol). Then solidNaBH(OAc)₃ (0.94 g, 4.4 mmol) was added. The mixture was stirred at roomtemperature for 1 h, then quenched with water and extracted with ether.The ether layer was washed with water and brine, then dried over MgSO₄,and evaporated to give 1.3 g of crude product, which was purified byflash column chromatography on silica gel eluting with 1:7 ethylacetate:hexane to give 1.0 g (87%) of the desired3[(3-phenoxyphenyl)[4-(N,N-diethylamino)phenyl]methyl]-amine product.HRMS calcd. for C₂₃H₂₆N₂O: 347.2123 [M+H]⁺, found 347.2124.

The 3-[(3-phenoxyphenyl)[4-(N,N-diethylamino)phenyl]methyl]amine (0.69g, 2.0 mmol) product from EX-631A and 1,1,1-trifluoro-2,3-epoxypropane(0.45 g, 4 mmol) were dissolved in 1 mL of acetonitrile. Ytterbium (III)trifluoromethanesulfonate (0.12 g, 0.1 mmol) was added, and the stirredsolution was warmed to 40° C. for 4 h, at which time HPLC analysisindicated that no secondary amine starting material remained. Thereaction was quenched with water and extracted with ether. The etherlayer was washed with water and brine, then dried over MgSO₄. The crudeproduct was purified by flash column chromatography on silica geleluting with 1:7:0.01 ethyl acetate: hexane:ammonium hydroxide followedby reverse phase preparative HPLC eluting with 10% to 90% acetonitrilein water to give 160 mg (17%) of the desired3-[(3-phenoxyphenyl)-[[4-(N,N-diethylamino)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a yellow oil, >95% pure by HPLC analysis. ¹H NMR (CD₃OD)δ7.39 (d, 2H), 7.31 (d, 2H), 7.22 (m, 3H), 7.13 (d, 1H), 6.98 (t, 1H),6.75 (dd, 2H), 6.47 (dd, 1H), 6.20 (d, 1H), 4.03 (m, 1H), 3.90 (s, 2H),3.58 (m, 4H), 3.36 (dd, 1H), 3.12 (dd, 1H), 1.05 (t, 6H). ¹⁹F NMR(CD₃OD) δ−80.51 (d, 3F). HRMS calcd. 459.2259 [M+H]⁺, found: 459.2250.

EXAMPLE 632

N-[2-chloro-6-(p-fluorophenoxy)-1,3,5-triazin-4-yl]-3-[[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-632A) 3-Trifluoromethoxybenzenemethanamine (1.15g, 6 mmol) and1,1,1-trifluoro-2,3-epoxypropane (0.67 g, 6 mmol) were combined andstirred at 80° C. for 1.5 h. The mixture was cooled to room temperature,and the resulting solid was recrystallized from hot hexanes. The whitesolid was isolated by vacuum filtration and washed with cold hexanes togive 0.67 g (37%) of pure3-[[[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.¹H NMR (CDCl₃) δ7.37 (t, 1H), 7.24 (d, 1H), 7.15 (m, 2H), 3.99 (m, 1H),3.85 (d, 2H), 2.98 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 1H). ¹⁹F NMR(CDCl₃) δ−58.19 (s, 3F), −78.88 (s, 3F). HRMS calcd. for C₁₁H₁₁F₆NO₂:304.0772 [M+H]⁺, found: 304.0794.

EX-632B) To a solution of 4-fluorophenol 1.00 g (8.92 mmol) in 30 mL oftetrahydrofuran at 0° C. was added a 60% dispersion of sodium hydride inmineral oil (0.36 g, 8.92 mmol). After 30 min, cyanuric chloride (1.64g, 8.92 mmol) was added as a heterogeneous mixture in tetrahydrofuran at0° C. The reaction mixture was allowed to slowly warm to roomtemperature. After 14 h, the mixture was cooled to 0° C., and asaturated aq. NH₄Cl solution was added. The aqueous solution wasextracted with diethyl ether (3×50 mL). The combined ether extracts werewashed with brine, dried (MgSO₄), and concentrated in vacuo to afford1.34 g (58%) of the desired2,4dichloro-6-(4-fluorophenoxy)-1,3,5-triazine product as an off whitesolid which was taken on to the next step without purification. MSm/z=260 [M+H]⁺.

To a stirred solution of aminopropanol from EX-632A (0.100 g, 0.330mmol) in N,N-dimethylformamide at 0° C. was added the2,4-dichloro-(4-fluorophenoxy)-1,3,5-triazine ether product from EX-632B(0.086 g, 0.330 mmol) as a solution in N,N-di-methylformamide. Thereaction mixture was allowed to slowly warm to room temperature. After14 h, the reaction mixture was cooled to 0° C., and a saturated aq.NaHCO₃ solution was added. After stirring the reaction mixture for 30min at room temperature, the aqueous layer was extracted with ether(3×30 mL). The combined ether extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to give a yellow oil. The cruderesidue was purified by column chromatography on silica gel eluting with20% ethyl acetate in hexanes to give 0.075 g (43%) of the desiredN-[2-chloro-6-(p-fluorophenoxy)-1,3,5-triazin-4-yl]-3-[[[3-(trifluoromethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a pale yellow oil. HRMS calcd. for C₂₀H₁₄ClF₇N₄O₃: 526.0643[M⁺], found: 526.0632. ¹H NMR (C₆D₆) δ6.95 (s, 1H), 6.63 (m, 14H), 4.74(d, 1H), 4.37 (d, 1H), 4.16 (d, 1H), 4.00 (d, 2H), 3.73 (m, 1H), 3.48(m, 2H), 3.26 (m, 2H), 3.12 (m, 2H).

EXAMPLE 633

3-[[3-(2-methyl-5-pyridyloxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol

EX-633A) 3-Bromoaniline (2.15 g, 12.5 mmol) and1,1,1-trifluoro-2,3-epoxypropane (1.0 g, 8.9 mmol) were placed in asealed vial, heated to 70° C. and stirred for 1 h under an atmosphere ofnitrogen. The crude product was purified by flash column chromatographyon silica gel eluting with CH₂CH₂:hexane (2:1) to give 2.11 g (84%) ofthe desired 3[(3-bromophenyl)amino]-1,1,1-trifluoro-2-propanol productas a light amber oil, 98% pure by HPLC analysis. MS m/z=284/286 [M+H]⁺.

EX-633B) The 3[(3-bromophenyl)amino]-1,1,1-trifluoro-2-propanol (1.14 g,4 mmol) from EX-633A and 3-(trifluoromethoxy)benzaldehyde (0.78 g, 4.1mmol) were dissolved in dichloroethane (18 mL). Acetic acid (0.253 mL,4.2 mmol) and solid NaBH(OAc)₃ (1.07 g, 5.05 mmol) were added. Themixture was stirred at room temperature for 3 h. then acidified with 1 NHCl solution. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide,the mixture was extracted with methylene chloride. The organic layer waswashed with brine and water, then dried over anhydrous MgSO₄, andevaporated to give 1.12 g (62%) of the desiredN-3-bromophenyl-[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a brown oil, which was greater than 80% pure by reverse phaseHPLC analysis. HRMS calcd. for C₁₇H₁₄NO₂F₆Br 458.0190 [M+H]⁺, found:458.0199.

The3[(3-bromophenyl)[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(500 mg, 1.1 mmol) product from EX-633B and 5-hydroxy-2-methylpyridine(262 mg, 2.4 mmol) were dissolved in dimethylacetamide (6 mL). Cs₂CO₃(1.0 g, 3.1 mmol) and (CuCF₃SO₃)₂C₆H₆ (150 mg) were added, and themixture was heated to 105° C. for 96 h under an atmosphere of nitrogen,at which time HPLC analysis indicated that most of the startingmaterials had been consumed. After adding water, the reaction mixturewas extracted with ether, and the ether extracts were washed with brineand dried over anhydrous MgSO₄. The crude product was purified by flashcolumn chromatography on silica gel eluting with ethyl acetate:hexane(1:12) to give 326 mg (61%) of the desired3-[[3-(2-methyl-5-pyridyloxy)phenyl][[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a light amber oil, 99% pure by HPLC analysis. ¹H NMR (CDCl₃)δ8.00 (s, 1H), 7.29 (t 1H), 6.99 (s, 1H), 7.02-7.15 (m, 5H), 6.46 (dd,1H), 6.29 (t, 1H), 6.25 (dd, 1H), 4.88 (br s, 1H), 4.67 (ABq, 2H), 4.36(m, 1H), 3.88 (dd, 1H), 3.56(dd, 1H), 2.49 (s, 3H). ¹⁹F NMR (CDCl₃)δ−58.2, (s, 3F), −79.1 (d, 3F). HRMS calcd. for C₂₃H₂₀N₂O₃F₆: 487.1456[M+H]⁺, found: 487.1425.

EXAMPLE 634

3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-634A) Dinitrobenzene (1.68 g, 10 mmol) and 4-fluorophenol (1.13 g, 10mmol) were dissolved in anhydrous dimethylsulfoxide (25 mL), andpowdered cesium carbonate (8 g, 24.8 mmol) was added. The mixture wasstirred and heated to 100° C. using a reflux condenser under a nitrogenatmosphere. After 16 h, the mixture was diluted with water (120 mL), andthe aqueous layer was extracted with diethyl ether (4×60 mL). Thecombined ether layers were washed with 3% HCl, 5% sodium hydroxide. andwater, then dried over anhydrous MgSO₄. The ether was removed in vacuo,and the recovered oil was purified by flash column chromatography onsilica gel eluting with ethyl acetate in hexane (1:25) to give 1.68 g(69%) of the desired 3-(4-fluorophenoxy)nitrobenzene product as orangecrystals, 97% pure by HPLC analysis. MS m/z=234 [M+H]⁺.

EX-634B) 3-(4-Fluorophenoxy)nitrobenzene (1.15 g, 4.93 mmol) fromEX-634A was dissolved in ethanol (45 mL), and the solution washydrogenated for 4 h in the presence of 5% palladium on charcoal. Afterthe mixture was filtered through celite, the ethanol was removed invacuo. The product was purified by flash column chromatography on silicagel eluting with ethyl acetate in hexane (1:10) to give 0.92 g (90%) of3-(4-fluorophenoxy)aniline as a yellow oil, 99% pure by HPLC analysis.HRMS calcd. for C₁₂H₁₁FNO: 204.0824 [M+H]⁺, found: 204.0837.

EX-634C) The 3-(4-fluorophenoxy)aniline (812 mg, 4 mmol) from EX-634Band 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (888 mg, 2 mmol) weredissolved in dichloroethane (15 mL) and acetic acid (0.25 mL, 4.2 mmol),then solid NaBH(OAc)₃ (1.01 g, 5 mmol) was added. The mixture wasstirred at room temperature for 3 h, then acidified with 1 N HCl. Afterneutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture wasextracted with methylene chloride. The organic layer was washed withbrine and water, then dried over anhydrous MgSO₄, and evaporated to give1.32 g (78%) of the desired ofN-[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amineproduct as a brown oil, which was greater than 90% pure by reverse phaseHPLC analysis. MS m/z=410 [M+H]⁺.

TheN-[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine(612 mg, 1.5 mmol) product from EX-634C and1,1,1-trifluoro-2,3-epoxypropane (268 mg, 2.4 mmol) were dissolved in1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (43mg, 0.07 mmol) was added, and the stirred solution was warmed to 40° C.for 2.5 h under an atmosphere of nitrogen, at which time HPLC analysisindicated that no secondary amine starting material remained. Thereaction was quenched with water and extracted with ether. The etherlayer was washed with brine and water, then dried over anhydrous MgSO₄.The ether was removed in vacuo, and the crude product was purified byflash column chromatography on silica gel eluting with ethyl acetate inhexane (1:11) to give 633 mg (81%) of the desired3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a yellow oil, 99% pure by HPLC analysis. ¹H NMR(CDCl₃) δ7.35(t, 1H), 7.15 (m, 3H), 6.98 (m, 5H), 6.49 (dd, 1H), 6.38 (dd, 1H), 6.33(m, 1H), 5.92 (tt, 1H), 4.67 (ABq, 2H), 4.37 (m, 1H), 3.91 (dd, 1H),3.59 (dd, 1H), 2.48 (d, 1H). ¹⁹F NMR (CDCl₃) δ−79.2 (d, 3F), −88.5 (m,2F), −120.33 (m, 1F), −137.2 (dt, 2F). HRMS calcd. for C₂₄H₁₉F₈NO₃:522.1315 [M+H]⁺, found: 522.1297.

Additional examples3-[(aryloxyphenyl)[[phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols areprepared by one skilled in the art using similar methods, as shown inExample Tables 39 and 40.

Example Table 39. 3-[(aryloxyphenyl)[[phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. R_(SUB1) R_(SUB2) Mass [M + H]⁺ [M +H]⁺ 635 4-F 3-OH 422.1379 422.1396 636 4-F 3-SCF₃ 505.0946 505.0927 6374-CH₃ 3-SCF₃ 502.1275 502.1261 638 3,4-F₂ 3-OCF₂CF₂H 540.1221 540.1248639 2,4-F₂ 3-OCF₂CF₂H 540.1221 540.1194 640 4-F 4-CF₃ 474.1304 474.1300

Example Table 40. 3-[[(3-aryloxy)-5-(trifluoromethyl)phenyl]][phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Ex. Mass Observed Mass No. R_(SUB1) R_(SUB2) [M + H]⁺ [M +H]⁺ 641 4-F 3-CF₃ 542.1178 542.1205 642 4-F 3-SCF₃ 574.0898 574.0899 6434-F 3-OCF₃ 558.1127 558.1137 644 4-F 3-OCF₂CF₂H 590.1189 590.1212

EXAMPLE 645

3-[(3-phenoxyphenyl)[[3-(isopropoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-645A) 3-Hydroxybenzaldehyde (5.60 g, 45.9 mmol) and 2-iodopropane(7.86 g, 46.2 mmol) were dissolved in 50 mL of isopropanol. Potassiumcarbonate (20 g, 145 mmol) was added, and the mixture was heated toreflux for 8 h, at which time TLC analysis indicated that the reactionhad gone to completion. Water was added to dissolve all solids, and themixture was extracted with ether (3×). The combined ether layer waswashed with water, 2 M NaOH, again with water until clear (4×), andfinally with brine. The solution was dried over MgSO₄, filtered, andevaporated to give 5.03 g (67%) of the desired 3-isopropoxybenzaldehydeproduct as a pale oil. ¹H NMR (C₆D₆) δ9.62 (s, 1H), 7.29 (s, 1H), 7.03(m, 1H), 6.91 (t, 1H), 6.84 (m, 1H), 4.03 (septet, 1H), 0.96 (d, 6H).

EX-645B) The 3-isoproxybenzaldehyde (0.780 g, 4.75 mmol) product fromEX-645A and 3-phenoxyaniline (0.881 g, 4.76 mmol) were combined in 20 mLof methanol, then solid NaCNBH₃ (0.238 g, 3.79 mmol) was added, and themixture was stirred until uniform. Acetic acid (2 ml) was added, and themixture was stirred at room temperature overnight, then quenched withwater, made basic with potassium carbonate, and extracted with ether(3×). The combined ether layers were washed with water and brine, driedover MgSO₄, filtered, and evaporated to give 1.32 g (84%) of the desiredN-(3-phenoxyphenyl)-[[3-isopropoxyphenyl]methyl]amine product as anamber oil. ¹H NMR (C₆D₆) δ6.6-7.1 (m, 10H), 6.44 (m, 1H), 6.25-6.00 (dd,1H), 6.15 (m, 1H), 4.25 (s, 1H), 4.19 (m, 1H), 3.80 (s, 1H), 2.65 (s,1H), 1.07 (m, 6H). MS m/z=333 [M⁺].

The N-(3-phenoxyphenyl)-[[3-isopropoxyphenyl]methyl]amine (0.528 g, 1.59mmol) product from EX-645B and 1,1,1-trifluoro-2,3-epoxypropane (0.506g, 4.51 mmol) were heated to 90° C. in a sealed container for 2 d underan argon atmosphere. The resulting mixture was eluted from silica gelwith an ethyl acetate in hexane gradient (0-10% ethyl acetate) andfractions were pooled after TLC analysis to give 197 mg (28%) of thedesired3-[(3-phenoxyphenyl)[[3-(isopro-poxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as clear, colorless oil. HRMS calcd. for C₂₅H₂₆F₃NO₃: 446.1943[M+H]⁺, found: 446.1936. ¹H NMR (C₆D₆) δ6.9-7.1 (m, 6H), 6.84 (tt, 1H),6.74 (s, 1H), 6.66 (dd, 1H), 6.61 (d, 1H), 6.56 (t, 1H), 6.41 (td, 2H),4.33 (s, 2H), 4.17 (septet, 1H), 3.91 (br s, 1H), 3.56 (dd, 1H), 3.31(m, 1H,), 2.8 (br s, 1H). 1.06 (s, 6H). ¹⁹F NMR (C₆D₆) δ−78.85 (d, 3F).

Additional examples of3-[aryloxyphenyl[[3-aryl]methyl]amino]-1,1,1-trifluoro-2-propanols areprepared by one skilled in the art using similar methods, as shown inExample Table 41.

Example Table 41. 3-[aryloxyphenyl[[3-aryl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Observed Ex. Calculated Mass No. R_(SUB1) R_(SUB2) Mass [M + H]⁺ [M +H]⁺ 646 F ethyl 450.1692 450.1682 647 F isopropyl 464.1849 464.1867 648F n-propyl 464.1849 464.1820 649 F n-butyl 478.2005 478.2015 650 Fsec-butyl 478.2005 478.1880 651 F —CH₂-cyclopropyl 476.1849 476.1857 652F isobutyl 478.2005 478.1970 653 F cyclopentyl 490.2005 490.1998

EXAMPLE 654

3-[(3-phenoxyphenyl)[[3-(1,1,1-dimethylethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-654A) 3-Hydroxybenzaldehyde (4.08 g, 33.4 mmol) was slurried in 50 mLof anhydrous CH₂Cl₂ and added to t-butyl-2,2,2-trichloroacetimidate(25.0 g, 114 mmol) in 200 mL of anhydrous cyclohexane with an additional50 mL of CH₂Cl₂ used in transfer. The mixture was stirred under nitrogenuntil uniform, then boron trifluoride diethyl etherate (0.50 mL, 4 mmol)was added via syringe and stirring was continued for 1 h. Powderedsodium bicarbonate (50 g, 0.6 mol) was added, and the solution wasfiltered through a silica gel plug, washing the plug with hexane. Thesolvent was evaporated to give crude product 3.54 g (59%) as an amberoil (85% pure by GC analysis). Chromatography on silica gel eluting with0-10% ethyl acetate in hexane gave 1.88 g (32%) of pure3-t-butoxybenzaldehyde product as a colorless oil. ¹H NMR (C₆D₆) δ9.59(s, 1H), 7.44 (br s, 1H), 7.20 (d t, 1H), 6.92 (m, 2H), 1.07 (s, 9H).

EX-654B) The 3-t-butoxybenzaldehyde (0.585 g, 3.27 mmol) product fromEX-654A and 3-phenoxyaniline (0.595 g, 3.21 mmol) were combined in 50 mLof THF, then solid NaBH(OAc)₃ (0.860 g, 4.06 mmol) was added, and themixture was stirred until uniform. Acetic acid (0.2 g, 3.33 mmol) wasadded, and the mixture was stirred at room temperature for 4 h, thenquenched with 5% aq. NaHCO₃. The aqueous layer was separated andextracted twice with ether. The combined ether layers were washed withwater and brine, dried over MgSO₄, filtered, and evaporated to give 1.29g (115%) of crude product as a brown oil. Chromatography on silica geleluting with 0-10% ethyl acetate in hexane gave 464 mg (40%) of thedesired N-(3-phenoxyphenyl)[[3-(1,1-dimethyl-ethoxy)phenyl]methyl]amineproduct as a colorless oil, pure by TLC. MS m/z=347 [M⁺].

The N-(3-phenoxyphenyl)[[3-(1,1-dimethylethoxy)phenyl]methyl]amine(0.270 g, 0.78 mmol) product from EX-654B was dissolved in 2 mL ofacetonitrile. Ytterbium triflate (16 mg, 0.026 mmol) was added in 0.5 mLof acetonitrile, and the mixture was stirred under nitrogen.1,1,1-Trifluoro-2,3-epoxypropane (0.105 g, 0.94 mmol) was added, thevial was sealed and heated to 45° C. After 24 h, TLC analysis showed 50%conversion, so additional 1,1,1-trifluoro-2,3-epoxypropane (88.6 mg,0.79 mmol) was added and heating continued for an additional 24 h. Theresulting mixture was eluted from silica gel with an ethyl acetate inhexane gradient (1.5-7% ethyl acetate). Fractions were pooled based onTLC analysis to give 150 mg (42%) of the desired3-[(3-phenoxy-phenyl)[[3-(1,1-dimethylethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a clear, colorless oil, and an additional 60 mg (17%) wasobtained as an amber oil. HRMS calcd. for C₂₆H₂₈F₃NO₃: 460.2100 [M+H]⁺,found: 460.2103. ¹H NMR (C₆D₆) δ6.78-7.08 (m, 9H), 6.68 (d, 1H), 6.55(t, 1H), 6.43 (dd, 1H), 6.34 (dd, 1H), 4.23 (s, 2H), 3.81 (m, 1H), 3.48(dd, 1H), 3.24 (m, 1H), 2.25 (br s, 1H), 1.07 (s, 9H). ¹⁹F NMR (C₆D₆)δ−78.92 (d, 3F).

EXAMPLE 655

3-[(3-phenoxyphenyl)[[3-(2-hydroxy-3,3,3-trifluoro-n-propoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-655A) The 3-(phenoxy)aniline (555 mg, 3 mmol) and3-hydroxybenzaldehyde (366 mg, 3 mmol) were dissolved in 7 mL of1,2-dichloroethane. Acetic acid (0.189 mL, 3.15 mmol) and solidNaBH(OAc)₃ (1.01 g, 5 mmol) were added. The mixture was stirred at roomtemperature for 3 h, then acidified with 1 N HCl solution. Afterneutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture wasextracted with methylene chloride. The organic layer was washed withbrine and water, then dried over anhydrous MgSO₄, and evaporated to give609 mg (69%) of the desiredN-(3-phenoxyphenyl)[[3-hydroxyphenyl]methyl]amine product as a brownoil, which was greater than 90% pure by reverse phase HPLC analysis. MSm/z=291.

The N-(3-phenoxyphenyl)[[3-hydroxypheny]methyl]amine (400 mg, 1.35 mmol)product from EX-655A and 1,1,1-trifluoro-2,3-epoxypropane (348 mg, 3mmol) were placed in a sealed vial, then stirred and heated to 95° C.for 15 h under an atmosphere of nitrogen. The vial was cooled, and more1,1,1-trifluoro-2,3-epoxypropane (112 mg, 1 mmol) was added. The vialwas sealed, then stirred and heated to 95° C. for a further 20 h underan atmosphere of nitrogen. The crude product was purified by flashcolumn chromatography on silica gel eluting with ethyl acetate in hexane(1:6) to give 518 mg (77%) of the desired3-[(3-phenoxyphenyl)[[3-(2-hydroxy-3,3,3-trifluoro-n-propoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a light amber oil, 98% pure by HPLC analysis. ¹H NMR (CDCl₃)δ7.20-7.32 (m, 3H), 7.14 (t, 1H), 7.07 (t, 1H), 6.95 (d, 2H), 6.80 (m,2H), 6.74 (s, 1H), 6.48 (dd, 1H), 6.38 (m, 2H), 4.59 (ABq, 2H), 4.31 (m,1H), 4.18 (dd, 1H), 4.10 (dd, 1H), 3.83 (dd, 1H), 3.54 (dd, 1H), 2.92(d, 1H), 2.61 (d, 1H). ¹⁹F NMR (CDCl₃) δ−78.0 (d, 3F), −79.2 (d, 3F).HRMS calcd. for C₂₅H₂₃F₆NO₄: 516.1611 [M+H]⁺, found: 516.1618.

EX-655B) Another example, 3-[3-(4-fluorophenoxy)phenyl[[3-(2-hydroxy-3,3,3-trifluoro-n-propoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol,was prepared by a similar method using 3-(4-fluorophenoxy)aniline as thestaring material. HRMS calcd. for C₂₅H₂₂F₇NO₄: 534.1515 [M+H]⁺, found:534.1505.

EXAMPLE 656

3-[[3-(4-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-656A) 3-Aminophenol (5.0 g, 45.8 mmol) and4-bromo-α,α,α,-trifluorotoluene (14.0 g, 62.2 mmol) were dissolved inanhydrous dimethylacetamide (20 mL), then anhydrous cesium carbonate (30g, 92.3 mmol) and copper triflate benzene complex (200 mg) were added.The mixture was stirred and heated to 85° C. using a reflux condenserunder an argon atmosphere. After 16 h, the mixture was diluted withwater (120 mL), and the aqueous layer was extracted with diethyl ether(4×60 mL). The combined ether layers were washed with 3% HCl, 5% NaOHand water, then dried over anhydrous MgSO₄. The ether was removed invacuo, and the recovered oil purified by flash column chromatography onsilica gel eluting with ethyl acetate in hexane (1:8) to give 6.8 g(59%) of the desired 3-(4-trifluoromethylphenoxy)aniline product as ayellow oil, which solidified to a yellow powder, 98% pure by HPLCanalysis. HRMS calcd. for C₁₃H₁₀F₃NO: 254.0792 [M+H]⁺, found: 254.0798.

EX-656B) The 3-(4trifluoromethylphenoxy)aniline (632 mg, 2.5 mmol) fromEX-656A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (555 mg, 2.5 mmol)were dissolved in 6 mL of dichloroethane and glacial acetic acid (0.15mL, 2.8 mmol), and solid NaBH(OAc)₃ (1.01 g, 5 mmol) was added. Themixture was stirred at room temperature for 3 h, then acidified with 1 NHCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, themixture was extracted with CH₂Cl₂ (3×20 mL). The organic layer waswashed with brine and water, then dried over anhydrous MgSO₄, andevaporated to give 861 mg (75%) of the desiredN-3-(4-trifluoromethylphenoxy)-phenyl[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amineproduct as a brown oil, which was greater than 90% pure by reverse phaseHPLC analysis. MS m/z=460 [M+H]⁺.

The N-3-(4trifluoromethylphenoxy)-phenyl[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amine (689 mg, 1.5 mmol) product from EX-656B and1,1,1-trifluoro-2,3-epoxypropane (252 mg, 2.25 mmol) were dissolved in1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (43mg, 0.07 mmol) was added, and the stirred solution was warmed to 50° C.for 2.5 h under an atmosphere of nitrogen, at which time HPLC analysisindicated that no secondary amine starting material remained. Thereaction was quenched with water and extracted with ether. The etherlayer was washed with brine and water, then dried over anhydrous MgSO₄.The crude product was purified by flash column chromatography on silicagel eluting with ethyl acetate in hexane (1:12) to give 520 mg (61%) ofthe desired3-[[3-(4-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a yellow oil, 99% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.49(d, 2H), 7.30 (t, 1H), 7.20 (t, 1H), 7.07 (m, 2H), 7.00 (s, 1H), 6.95(d, 2H), 6.55 (dd, 1H), 6.43 (dd, 1H), 6.34 (t, 1H), 5.87 (tt, 1H), 4.64(ABq, 2H), 4.33 (m, 1H), 3.88 (dd, 1H), 3.58 (dd, 1H), 2.43 (bs, 1H).¹⁹F NMR (CDCl₃) δ−62.2 (s, 3F), −79.2 (d, 3F), −88.6 (m, 2F), −137.2(dt, 2F). HRMS calcd. for C₂₅H₁₉F₁₀NO₃: 572.1282 [M+H]⁺, found:572.1268.

Additional examples of3-[aryloxyphenyl[[phenyl]methyl]amino]-1,1,1-tri-fluoro-2-propanols areprepared by one skilled in the art using similar methods, as shown inExample Table 42.

Example Table 42. 3-[Aryloxyphenyl[[phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols

Ex. Calculated Mass Observed Mass No. R_(SUB1) [M + H]⁺ [M + H]⁺ 657 CN529.1362 529.1364 658 OCF₃ 588.1233 588.1241

EXAMPLE 659

3-[(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-659A) 3-Hydroxybenzaldehyde (12.22 g, 0.10 mol) and 100 mL ofanhydrous methanol were combined in a 250 mL round-bottom flask. Sodiummethoxide was slowly added as a 25 wt. % solution in methanol (21.61 g,0.10 mol), and the methanol was removed under vacuum. Then2,2,2-trifluoroethyl-p-toluenesulfonate (25.42 g, 0.10 mol) was added,the flask was purged with nitrogen, and 100 mL of N-methyl pyrrolidinewas added. The solution was stirred for 24 h at 90° C., quenched withwater, and extracted with ether (3×). The combined ether layers werewashed with 1 M NaOH (2×), water, and brine, dried over MgSO₄, filtered,and evaporated to give 11.72 g of crude product. Chromatography oversilica gel eluting with 0-10% ethyl acetate in hexane followed by asecond chromatography with toluene gave 5.24 g (26%) of the desired3-(2,2,2-trifluoroethoxy)benzaldehyde product as a pale oil. ¹H NMR(C₆D₆) δ9.61 (s, 1H), 7.14 (d, 1H), 7.06 (s, 1H), 6.97 (t, 1H), 6.75 (m,1H), 3.75 (m, 2H). ¹⁹F NMR (C₆D₆) δ−74.45 (t, 3F).

EX-659B) The 3-(2,2,2-trifluoroethoxy)benzaldehyde (0.360 g, 1.76 mmol)product from EX-659A and 3-phenoxyaniline (0.326 g, 1.76 mmol) werecombined in 50 mL of cyclohexane with 3 Å molecular sieves (1 g) andstirred overnight at 80° C. The mixture was cooled, filtered, andevaporated, then dissolved in 50 mL of methanol and cooled to 0° C.Solid sodium borohydride (0.030 g, 0.79 mmol) was added in portions, andthe mixture was stirred overnight. The reaction was quenched with 5% aq.NaHCO₃ and extracted with ether (3×). The combined ether layers werewashed with water and brine, dried over MgSO₄, filtered, and evaporatedto give 0.50 g (76%) of the desiredN-(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amineproduct as an amber oil, >95% pure by normal phase HPLC analysis. MSm/z=373 [M⁺].

The N-(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amine(0.50 g, 1.35 mmol) product from EX-659B and1,1,1-trifluoro-2,3-epoxy-propane (1.0 ml, 11 mmol) were heated to 90°C. in a sealed container under argon for 2 d. The resulting mixture waseluted from silica gel with 4% ethyl acetate in hexane, and fractionswere pooled based on TLC analysis to give 134 mg (21%) of the desired3-[(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a clear, colorless oil. ¹H NMR (C₆D₆) δ6.80-7.08 (m, 7H),6.64 (d, 1H), 6.53 (bt, 1H), 6.49 (t, 1H), 6.44 (dd, 1H), 6.34 (dt, 2H),4.23 (s, 2H), 3.84 (m, 1H), 3.61 (m, 2H), 3.53 (dd, 1H), 3.20 (m, 1H),2.03 (d, 1H). ¹⁹F NMR (C₆D₆) δ−74.20 (t, 3F), −78.95 (d, 3F). HRMScalcd. for C₂₄H₂₁F₆NO₃: 486.1504 [M+H]⁺, found: 486.1498.

EXAMPLE 660

3-[(4-chloro-3-ethylphenoxy)phenyl[[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol.

EX-660A) Sodium pentafluoroethyl propionate (8.4 g, 50 mmol) and3-iodotoluene (5.5 g, 25 mmol) were dissolved in anhydrous DMF (300 mL).CuI (9.5 g, 50 mmol) was added, and the mixture was heated to 160° C.under nitrogen for 4 h. at which time a 15 mL fraction of a mixture ofDMF and 3-pentafluoroethyl toluene was collected. The distillate wasdiluted with Et₂O and was washed with brine. The ether layer was driedover MgSO₄, filtered and concentrated in vacuo to give 5.25 g (55%) ofthe desired 3-pentafluoroethyl-toluene product as a colorless oil. ¹HNMR (CDCl₃) δ7.36 (m, 4H), 2.40 (s, 3H). ¹⁹F NMR (CDCl₃) δ−85.2 (s, 3F),−115.2 (s, 2F).

EX-660B) The 3-pentafluoroethyl-toluene (2.9 g, 13.8 mmol) product fromEX-660A and N-bromosuccinimide (2.5 g, 13.8 mmol) were dissolved in CCl₄(25 mL). AIBN (50 mg) was added, and the mixture was refluxed for 3.5 hunder N₂. The reaction mixture was cooled to room temperature anddiluted with water. The layers were separated, and the organic layer waswashed with brine, dried with anhydrous MgSO₄, filtered, andconcentrated in vacuo to give 3.4 g (87%) of a colorless oil. The ¹H NMRspectrum indicated that the crude product contained3-pentafluoroethyl-benzylbromide (70%), the benzyl dibromide (10%) and3-pentafluoroethyl toluene (20%). ¹H NMR (CDCl₃) δ7.60 (m, 2H), 7.50 (m,2H), 4.50 (s, 2H). ¹⁹F NMR (CDC13) δ−85.1 (s, 3F), −115.4 (s, 2F).

EX-660C) A solution of 3-(4chloro-3-ethylphenoxy)aniline (1.7g, 6.9mmol) was prepared in cyclohexane (13 mL). A solution of crude3-pentafluoroethyl benzylbromide (1 g, 3.5 mmol) product from EX-660B incyclohexane (10 mL) was added dropwise over 3 min. The reaction mixturewas refluxed under N₂ for 24 h and then was cooled to room temperature.The mixture was diluted with Et₂O and saturated aqueous NaHCO₃. Thelayers were separated, and the aqueous layer was extracted with Et₂O.The organic layer was washed with brine, dried with anhydrous MgSO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel eluting with hexanes in ethyl acetate(95:5) which gave 0.56 g (35%) of the desiredN-[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoro-ethyl)phenyl]methyl]amineproduct as an amber oil. ¹H NMR (CDCl₃) δ7.53 (m, 4H), 7.27 (d, 1H),7.15 (t, 1H), 6.93 (d, 1H), 6.77 (dd, 1H), 6.41 (tt, 2H), 6.30 (t, 1H),4.41 (s, 2H), 2.73 (q, 2H), 1.23 (t, 3H). ¹³C NMR (CDCl₃) δ158.6, 156.1,143.4, 141.3, 140.2, 131.3, 130.7, 130.4, 129.4, 128.1, 120.4, 117.8,108.8. 103.9, 48.5, 27.5, 14.1. ¹⁹F NMR (CDCl₃) δ−85.1 (s, 3F), −115.2(s, 2F). HRMS calcd. for C₂₃H₁₉ClF₅NO: 456.1154 [M+H]⁺, found: 456.1164.

TheN-[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amine(0.05 g, 0.11 mmol) product of EX-660C was dissolved in anhydrousacetonitrile (0.2 mL). 1,1,1-trifluoro-2,3-epoxypropane (0.1 g, 0.89mmol) and Yb(OTf)₃ (7 mg, 0.001 mmol) were added, and the reactionmixture was stirred under N₂ at 45° C. After 3 h, the reaction mixturewas cooled to room temperature and diluted with Et₂O and saturatedaqueous NaHCO₃. The layers were separated and the aqueous layer wasextracted with Et₂O. The ether layers were combined, washed with brine,dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. Theviscous oil was adsorbed onto silica gel and eluted with hexanes inethyl acetate (95:5) which gave 20 mg (32%) of the desired3-[(4-chloro-3-ethylphenoxy)phenyl[[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a viscous, colorless oil. ¹H NMR (CDCl₃) δ7.47 (m, 4H), 7.23(m, 3H), 6.90 (d, 1H), 6.72 (dd, 1H), 6.52 (d, 1H), 6.42 (m, 2H), 4.73(s, 2H), 4.39 (m, 1H), 3.91 (dd, 1H), 3.58 (m, 2H), 2.73 (q, 2H), 2.57(s, 1H), 1.22 (t, 3H). ¹⁹F NMR (CDCl₃) δ−79.2 (s, 3F), −84.9(s, 3F),−115.2 (s, 2F). HRMS calcd. for C₂₆H₂₂ClF₈NO₂: 568.1290 [M+H]⁺. found:568.1314.

EXAMPLE 661

6-fluoro-3,4-dihydro-4-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2-(trifluoromethyl)-2H-1,4benzoxazine

EX-661A) A mixture of 2,5-difluoroaniline (2.58 g, 20 mmol) and3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (4.44 g, 20 mmol) incyclohexane (50 mL) was heated under reflux for 5 h using a Dean-Starktrap to remove water. The solvent was removed in vacuo, and the residuewas dissolved in methanol (30 mL). The solution was stirred and cooledto 0° C., then sodium borohydride was added (1.32 g, 35 mmol). Themixture was allowed to warm to room temperature and stirred for 2 h,then acidified with 1 N HCl. After neutralizing to pH 7.5 with 2.5 Nsodium hydroxide, the mixture was extracted with diethyl ether (3×20mL). The organic layer was washed with brine and water, then dried overanhydrous MgSO₄, and evaporated to give 5.7 g (86%) of the desiredN-(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amineproduct as a brown oil, which was greater than 90% pure by reverse phaseHPLC analysis. MS m/z=336 [M⁺].

EX-661 B) TheN-(2.5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-amine(2.22 g, 6.67 mmol) product from EX-661A and1,1,1-trifluoro-2.3-epoxypropane (1.12 g, 10 mmol) were dissolved in 1.5mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.21 g,0.33 mmol) was added, and the stirred solution was warmed to 50° C. for2 h under an atmosphere of nitrogen, at which time HPLC analysisindicated that no secondary amine starting material remained. Thereaction was quenched with water and extracted with ether. The etherlayer was washed with water and brine, then dried over anhydrous MgSO₄.The crude product was purified by flash column chromatography on silicagel eluting with ethyl acetate in hexane (1:10) to give 2.49 g (84%) ofthe desired3[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a yellow oil, 99% pure by HPLC analysis. HRMS calcd. forC₁₈H₁₄F₉NO₂: 448.0959 [M+H]⁺, found: 448.0940.

The3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(200 mg, 0.45 mmol) product from EX-661B was dissolved in anhydrousdimethylformamide (20 mL), and powdered K₂CO₃ (180 mg) was added. Themixture was stirred and heated to 145° C. for 15 h. The mixture wasdiluted with water (60 mL) and extracted into ether (2×40 mL), which waswashed with brine and water. The ether solution was dried over anhydrousMgSO₄, and the ether was removed in vacuo. The crude product waspurified by flash column chromatography on silica gel eluting with ethylacetate in hexane (1:15) to give 86.9 mg (48%) of the desired6-fluoro-3,4-dihydro-4-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2-(tri-fluoromethyl)-2H-1,4-benzoxazineproduct as a yellow oil, 98% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.39(t, 1H), 7.17 (m. 3H), 6.88 (m 1H), 6.41 (m, 2H), 5.92 (tt, 1H), 4.54(m, 1H), 4.45 (s, 2H), 3.44 (m, 2H). ¹⁹F NMR (CDCl₃) δ−77.7 (d, 3F),−88.6 (m, 2F), −120.28 (m, 1F), −137.2 (dt, 2F). HRMS calcd. forC₁₈H₁₃F₈NO₂: 428.0899 [M+H]⁺, found: 428.0910.

EXAMPLE 662

2,2,2-trifluoro-1-[[(3-fluorophenyl)[3-(trifluoromethyl)benzoyl]amino]-methyl]ethyl 3-trinuoromethylbenzoate

EX-662A)3-[(3-fluorophenyl)[phenylmethyl]amino]-1,1,1-trifluoro-2-propanol (2.56g, 8.2 mmol) was dissolved in methanol (30 mL) and hydrogenated over 5%palladium on charcoal for 3 h. The mixture was filtered through celite,and the solvent was removed in vacuo to give 1.8 g (98%) of the desired3-[(3-fluorophenyl)amino]-1,1,1-trifluoro-2-propanol product as an oil,99% pure by HPLC analysis. MS m/z=224 [M+H]⁺.

The 3-[(3-fluorophenyl)amino]-1,1,1-trifluoro-2-propanol (446 mg, 2.0mmol) from EX-662A and triethylamine (544 mg) were dissolved inanhydrous CHCl₃ (30 mL) and cooled to 0° C. Then a solution of3-trifluoromethylbenzoyl chloride (1.04 g, 5.0 mmol) in anhydrous CHCl₃(6 mL) was added over a period of 15 min. The solution was stirred atroom temperature. After 14 h, the solution was washed with 5% NaHCO₃(2×20 mL) and brine (2×10 mL), and then dried over anhydrous MgSO₄.Removal of the solvent in vacuo gave 832 mg (73%) of the desired2,2,2-trifluoro-1-[[(3-fluoro-phenyl)[3-(trifluoromethyl)benzoyl]amino]methyl]ethyl3-trifluoromethyl-benzoate product as an amber oil, which was greaterthan 95% pure by reverse phase HPLC analysis. ¹H NMR (CDCl₃) δ7.25-8.39(m, 9H), 7.02 (q, 1H), 6.71 (m, 2H), 6.11 (m, 1H), 4.58 (dd, 1H), 4.35(dd, 1H). ¹⁹F NMR (CDCl₃) δ−64.4 (m, 6F), −77.4 (s, 3F), −111.3 (m, 1F).HRMS calcd. for C₂₅H₁₅F₁₀NO₃: 568.0970 [M+H]⁺, found: 568.0968.

EXAMPLE 663

N-(3-fluorophenyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-3-(trifluoromethyl)benzamide

A solution of2,2,2-trifluoro-1-[[(3-fluorophenyl)[3-(trifluoromethyl)benzoyl]amino]-methyl]ethyl3-trifluoromethyl-benzoate (600 mg, 1.06 mmol) from EX-662 in methanolwas treated with 28% ammonia solution (122 μL). The solution was stirredat room temperature for 10 h. The reaction was quenched with water andextracted with ether. The ether layer was washed with brine and water,then dried over anhydrous MgSO₄. The crude product was purified by flashcolumn chromatography on silica gel eluting with ethyl acetate in hexane(1:8) to give 255 mg (61%) of the desiredN-(3-fluorophenyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-3-(trifluoromethyl)benzamideproduct as a white powder, 97% pure by HPLC analysis. ¹H NMR (CDCl₃)δ7.56 (m, 3H), 7.32 (m 2H), 6.98 (m, 1H), 6.90 (m, 2H), 4.49 (dd, 1H),4.34 (d, 1H), 4.26 (m, 1H), 4.01 (dd, 1H). ¹⁹F NMR (CDCl₃) δ−64.7 (s,3F), −80.3 (s, 3F), −110 (m, 1F). HRMS calcd. for C₁₇H₁₂F₇NO₂: 396.0854[M+H]⁺, found: 396.0821.

EXAMPLE 664

2,2,2-trifluoro-1-[[[(3-fluorophenyl)[3-(trifluoromethyl)phenyl]-methyl]amino]methyl]ethyl Acetate

A solution of3-[(3-fluorophenyl)[[3-(3-trifluoromethyl)phenyl]methyl]amino]-1,1,1-tri-fluoro-2-propanol(200 mg, 0.52 mmol) from EX-1 in triethylamine (0.6 mL) and aceticanhydride (0.5 mL) was stirred and heated to 80° C. for 1 h. The mixturewas cooled and diluted with water (20 mL) and extracted into ether (2×40mL), which was washed with 0.1 N NaOH and water. The ether solution wasdried over anhydrous MgSO₄. The ether was removed in vacuo giving thedesired 2,2,2-trifluoro-1-[[[(3-fluorophenyl)[3-(trifluoromethyl)phenyl]methyl]amino]methyl]ethyl acetate product as an amber oil, 98%pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.42-7.59 (m, 3H), 7.38 (d 1H),7.18 (q, 1H), 6.42-6.56 (m, 3H), 5.69 (m, 1H), 4.64 (ABq, 2H), 3.89 (d,1H), 3.87(s, 1H), 1.98 (s, 3H). ¹⁹F NMR (CDCl₃) δ64.0 (s, 3F), −77.2 (s,3F), −112.9 (s, 1F). HRMS calcd. for C₁₉H₁₆F₇NO₂: 424.1148 [M+H]⁺,found: 424.1159.

EXAMPLE 665

1,1′-[methylenebis[3,1-phenylene[[[3-(trifluoromethoxy)phenyl]methyl]imino]]]bis[3,3,3-trifluoro-2-propanol]

EX-665A) A solution of 3,3′-diaminophenylmethane (1.48 g, 7.5 mmol) and3-trifluoromethoxy-benzaldehyde (2.85 g, 15 mmol) in cyclohexane (50 mL)was heated under reflux for 5 h using a Dean-Stark trap to remove water.The solvent was removed in vacuo, and the residue was dissolved inmethanol (30 mL). The solution was stirred and cooled to 0° C., andsolid sodium borohydride was added (0.87 g 23 mmol). The mixture wasallowed to warm to room temperature and stirred for 2 h, then acidifiedwith 1 N HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide,the mixture was extracted with diethyl ether (3×30 mL). The organiclayer was washed with brine and water, then dried over anhydrous MgSO₄,and evaporated to give 3.19 g (78%) of the desired3,3′-N,N′-bis(trifluoromethoxyphenyl)diamino-phenylmethane product as abrown oil, which was greater than 90% pure by reverse phase HPLCanalysis. MS m/z=546 [M⁺].

The amine (2.18 g, 4 mmol) product from EX-665A and1,1,1-trifluoro-2,3-epoxy-propane (0.67 g, 6 mmol) were combined in asealed vial and heated to 95° C. for 2 days, at which time HPLC analysisindicated that little secondary amine starting material remained. Theexcess oxirane was removed under nitrogen, and the crude product waspurified by flash column chromatography on silica gel eluting with ethylacetate in hexane (1:12) to give 2.0 g (67%) of the desired1,1′-[methylenebis[3,1-phenylene[[[3-(trifluoromethoxy)phenyl]methyl]imino]]]bis-[3,3,3-trifluoro-2-propanol]productas a light amber oil, 99% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.30(t, 2H), 7.10 (m, 6H), 7.02 (s, 2H), 6.58 (m, 4H), 6.52 (s, 2H), 4.60(s, 4H), 4.22 (m, 2H), 3.80 (s, 2H), 3.79 (dd, 2H), 3.48 (dd, 2H), 2.60(br s, 2H). ¹⁹F NMR (CDCl₃) δ−66.2 (s, 6F), −79.2 (d, 6F). HRMS calcd.for C₃₅H₃₀ F₁₂N₂O₄: 771.2092 [M+H]⁺, found: 771.2072.

EXAMPLE EX-666

4-[[(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-butanol

EX-666A) The 4amino-2-hydroxy-1,1,1-trifluorobutane (1.0 g, 7.0 mmol)from EX-611A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.5 g, 7.0mmol) were dissolved in 20 mL of dichloroethane and acetic acid (0.40mL, 7.7 mmol), then solid NaBH(OAc)₃ (1.8 g, 8.4 mmol) was added. Themixture was stirred at room temperature for 3 d, then quenched withwater and extracted with ether. The ether layer was washed with waterand brine, then dried over MgSO₄, and evaporated to give 1.6 g of crudeproduct, which was purified by reverse phase HPLC to give 0.90 g (37%)of the desired4-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-butanolproduct as a yellow oil. HRMS calcd. for C₁₃H₁₄F₇NO₂: 350.0991 [M+H]⁺,found: 350.0971.

The1,1,1-trifluoro[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-2-butanol(0.35 g, 1 mmol) from EX-666A, 3-(4-fluorophenoxy)bromobenzene (0.32 g,1.2 mmol), Pd₂(dba)₂ (18 mg, 0.02 mmol), (R,+) BINAP (49 mg, 0.08 mmol),and Cs₂CO₃ (0.46 g, 1.4 mmol) were mixed in 9 mL of toluene and heatedto 100° C. for over 2 weeks, at which time FABMS (m/z=536.3 [M+H]⁺)indicated that the desired4-[[(4-fluorophenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-tri-fluoro-2-butanolproduct had formed.

Based on the preceding procedures, other substituted3-[(N-aryl)-[[aryl]methyl]amino]-halo-2-propanols can be prepared by oneskilled in the art using similar methods, as shown in Example Tables 43,46, and 47. Substituted 3-[(N-aralkyl)-[[aralkyl]amino]-halo-2-propanolscan also be prepared by one skilled in the art using similar methods, asshown in Example Tables 44 and 45. Substituted3-[(N-aryl)-[[aryl]methyl]amino]-haloalkoxy-2-propanols can be preparedby one skilled in the art using similar methods, as shown in ExampleTable 48.

Example Table 43. 3-[(N-aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H]⁺ [M +H]⁺ 667 2-OCH₃ 4-CH₃ 340.1524 340.1492 668 2-OCH₃ 3-CH₃ 340.1524340.1527 669 2-OCH₃ 3-CF₃ 394.1242 394.1239 670 3-F 2-CF₃ 382.1042382.1029 671 3-F 2-CH₃ 328.1325 328.1319 672 4-CF₃ 4-CH₃ 378.1293378.1273 673 2-CF₃ 4-CH₃ 378.1293 378.1284 674 3-F 3-(3-CF₃-phenoxy)474.1304 474.1276 675 3-F 3-(4-OCH₃- 436.1536 436.1532 phenoxy) 676 3-F3-(4-Cl-phenoxy) 440.1040 440.1048 677 3-F 3,5-(CF₃)₂ 450.0916 450.0923678 2,3-difluoro 3-CH₃ 346.1230 346.1209 679 2-F, 3-CF₃ 4-CH₃ 396.1198396.1200 680 2-F, 3-CF₃ 3-CH₃ 396.1198 396.1180 681 2,3-difluoro 4-CH₃346.1230 346.1228 682 2-OCH₃ 4-CF₃ 394.1242 394.1246 683 3-OCF₃4-benzyloxy 486.1504 486.1538 684 3-phenoxy 2-NO₂, 4-Cl 467.9 467.9 6853-phenoxy 4-(3,4-Cl₂- 548 548 phenoxy) 686 3-phenoxy 4-OCH₃ 418 418 6873-phenoxy 3,4-(OCF₂CF₂O) 518.1202 518.1286 688 3-OCF₃ 3-CF₃ 448 448 6894-phenyl 3-CF₃ 440.1449 440.1430 690 3,5-(CF₃)₂ 3-phenoxy 524 524 6912,5-(CF₃)₂ 3-CF₃ 500 500 692 3-OH 3-OCF₃ 396.1034 396.1053 6933-[4-(propan- 3-OCF₂CF₂H 560.1672 560.1694 oyl)phenoxy]

Example Table 44. 3-[N-[(aryl)methyl]-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. R_(SUB1) R_(SUB2) Mass [M + H] [M + H]694 3-CH 3-OCF₃ 428.0852 428.0817 695 3-Br 3-OCH₃ 472.0347 472.0312 6962-F 2-CF₃ 396.1198 396.1193

Example Table 45. 3-[N-[(aryl)methyl]-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. R_(SUB1) R_(SUB2) Mass [M + H] [M + H]697 3-OCF₃ 3-OCF₃ 442.1253 442.1232

Example Table 46. 3-[N-(aryl)-N-(aralkyl)amino]-1,1,1,-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H]698 3-OCF₃- 2-methoxy- 500.1297 500.1295 benzyl dibenzofuran-3-yl 6993-OCF₃- 2-fluorenyl 468.1398 468.1374 benzyl

Example Table 47. 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. R_(SUB1)-N-R_(SUB2) Mass [M + H] [M +H] 700

280.0949 280.0938

Example Table 48. 3-[N-(aryl)-N-(aralkyl)amino]-1-haloalkoxy-2-propanols.

Ex. Calculated Observed Mass No. R_(SUB1) Mass [M + H] [M + H] 701 F584.1483 584.1473 702 CF₃ 634.1451 634.1432

Based on the preceding procedures, additional substituted3-[(N-aryl)-[[aryl]methyl]amino]-halo-2-propanols are prepared by oneskilled in the art using similar methods, as shown in the multiplesections of Example Table 49. Substituted4-[N-(aryl)-[(aryl)methyl]amino]-1,1,1,2,2-pentafluoro-3-butanols areprepared by one skilled in the art using similar methods, as shown inExample Table 50. Substituted3-[N-(aryl)-[(aryl)oxy]amino]-1,1,1-trifluoro-2-propanols are preparedby one skilled in the art using similar methods, as shown in ExampleTable 51. Substituted3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-butanols are preparedby one skilled in the art using similar methods, as shown in ExampleTable 52.

Substituted 3-[N,N′-(diaryl)amino]-1,1,1-trifluoro-2-propanols areprepared by one skilled in the art using similar methods, as shown inExample Table 53. Substituted2-[N-(aryl)-[(aryl)methyl]amino]-1-trifluoromethylcyclopentanols areprepared by one skilled in the art using similar methods, as shown inExample Table 54.

EXAMPLE TABLE 49 Substituted 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols

Ex. No. R_(SUB1)  703 3-isopropyl  704 2-Cl, 3-Cl  705 3-CF₃O  706 4-F 707 4-CH₃  708 2-F, 5-Br  709 3-CHF₂O  710 3-CH₃CH₂  711 3-CH₃, 5-CH₃ 712 3-(CH₃)₃C  713 4-F, 3-CH₃  714 3-Cl, 4-Cl  715 3,4-(CH₂)₄  7163-HCF₂CF₂O  717 H  718 3-(CH₃)₂N  719 3-cyclopropyl  720 3-(2-furyl) 721 3-CF₃CF₂  722 4-NH₂  723 3-CH₃, 4-CH₃, 5-CH₃  724 4-CH₃CH₂CH₂O  7252-NO₂

Ex. No. R_(SUB1)  726 3-isopropyl  727 2-Cl, 3-Cl  728 3-CF₃O  729 4-F 730 4-CH₃  731 2-F, 5-Br  732 2-Br, 5-F  733 3-CH₃CH₂  734 3-CH₃, 5-CH₃ 735 3-(CH₃)₃C  736 4-F, 3-CH₃  737 3-Cl, 4-Cl  738 3,4-(CH₂)₄  7393-HCF₂CF₂O  740 3-CHF₂O  741 3-(CH₃)₂N  742 3-cyclopropyl  7433-(2-furyl)  744 3-CF₃CF₂  745 4-NH₂  746 3-CH₃, 4-CH₃, 5-CH₃  7474-CH₃CH₂CH₂O  748 2-NO₂

Ex. No. R_(SUB1)  749 3-isopropyl  750 2-Cl, 3-Cl  751 3-CF₃O  752 4-F 753 4-CH₃  754 2-F, 5-Br  755 4-Cl, 3-CH₃CH₂  756 3-CH₃CH₂  757 3-CH₃,5-CH₃  758 3-(CH₃)₃C  759 4-F, 3-CH₃  760 3-Cl, 4-Cl  761 3,4-(CH₂)₄ 762 3-HCF₂CF₂O  763 3-CHF₂O  764 3-(CH₃)₂N  765 3-cyclopropyl  7663-(2-furyl)  767 3-CF₃CF₂  768 4-NH₂  769 3-CH₃, 4-CH₃, 5-CH₃  7704-CH₃CH₂CH₂O  771 2-NO₂

Ex. No. R_(SUB1)  772 3-isopropyl  773 2-Cl, 3-Cl  774 3-CF₃O  775 4-F 776 4-CH₃  777 2-F, 5-Br  778 4-Cl, 3-CH₃CH₂  779 3-CH₃CH₂  780 3-CH₃,5-CH₃  781 3-(CH₃)₃C  782 4-F, 3-CH₃  783 3-Cl, 4-Cl  784 3,4-(CH₂)₄ 785 3-HCF₂CF₂O  786 3-CHF₂O  787 3-(CH₃)₂N  788 3-cyclopropyl  7893-(2-furyl)  790 3-CF₃CF₂  791 4-NH₂  792 3-CH₃, 4-CH₃, 5-CH₃  7934-CH₃CH₂CH₂O  794 2-NO₂

Ex. No. R_(SUB1)  795 3-isopropyl  796 2-Cl, 3-Cl  797 3-CF₃O  798 4-F 799 4-CH₃  800 2-F, 5-Br  801 4-Cl, 3-CH₃CH₂  802 3-CH₃CH₂  803 3-CH₃,5-CH₃  804 3-(CH₃)₃C  805 4-F, 3-CH₃  806 3-Cl, 4-Cl  807 3,4-(CH₂)₄ 808 3-HCF₂CF₂O  809 3-CHF₂O  810 3-(CH₃)₂N  811 3-cyclopropyl  8123-(2-furyl)  813 3-CF₃CF₂  814 4-NH₂  815 3-CH₃, 4-CH₃, 5-CH₃  8164-CH₃CH₂CH₂O  817 2-NO₂

Ex. No. R_(SUB1)  818 3-isopropyl  819 2-Cl, 3-Cl  820 3-CF₃O  821 4-F 822 4-CH₃  823 2-F, 5-Br  824 4-Cl, 3-CH₃CH₂  825 3-CH₃CH₂  826 3-CH₃,5-CH₃  827 3-(CH₃)₃C  828 4-F, 3-CH₃  829 3-Cl, 4-Cl  830 3,4-(CH₂)₄ 831 3-HCF₂CF₂O  832 3-CHF₂O  833 3-(CH₃)₂N  834 3-cyclopropyl  8353-(2-furyl)  836 3-CF₃CF₂  837 4-NH₂  838 3-CH₃, 4-CH₃, 5-CH₃  8394-CH₃CH₂CH₂O  840 2-NO₂

Ex. No. R_(SUB1)  841 3-isopropyl  842 2-Cl, 3-Cl  843 3-CF₃O  844 4-F 845 4-CH₃  846 2-F, 5-Br  847 4-Cl, 3-CH₃CH₂  848 3-CH₃CH₂  849 3-CH₃,5-CH₃  850 3-(CH₃)₃C  851 4-F, 3-CH₃  852 3-Cl, 4-Cl  853 3,4-(CH₂)₄ 854 3-HCF₂CF₂O  855 3-CHF₂O  856 3-(CH₃)₂N  857 3-cyclopropyl  8583-(2-furyl)  859 3-CF₃CF₂  860 4-NH₂  861 3-CH₃, 4-CH₃, 5-CH₃  8624-CH₃CH₂CH₂O  863 2-NO₂

Ex. No. R_(SUB1)  864 3-isopropyl  865 2-Cl, 3-Cl  866 3-CF₃O  867 4-F 868 4-CH₃  869 2-F, 5-Br  870 4-Cl, 3-CH₃CH₂  871 3-CH₃CH₂  872 3-CH₃,5-CH₃  873 3-(CH₃)₃C  874 4-F, 3-CH₃  875 3-Cl, 4-Cl  876 3,4-(CH₂)₄ 877 3-HCF₂CF₂O  878 3-CHF₂O  879 3-(CH₃)₂N  880 3-cyclopropyl  8813-(2-furyl)  882 3-CF₃CF₂  883 4-NH₂  884 3-CH₃, 4-CH₃, 5-CH₃  8854-CH₃CH₂CH₂O  886 2-NO₂

Ex. No. R_(SUB1)  887 3-isopropyl  888 2-Cl, 3-Cl  889 3-CF₃O  890 4-F 891 4-CH₃  892 2-F, 5-Br  893 4-Cl, 3-CH₃CH₂  894 3-CH₃CH₂  895 3-CH₃,5-CH₃  896 3-(CH₃)₃C  897 4-F, 3-CH₃  898 3-Cl, 4-Cl  899 3,4-(CH₂)₄ 900 3-HCF₂CF₂O  901 3-CHF₂O  902 3-(CH₃)₂N  903 3-cyclopropyl  9043-(2-furyl)  905 3-CF₃CF₂  906 4-NH₂  907 3-CH₃, 4-CH₃, 5-CH₃  9084-CH₃CH₂CH₂O  909 2-NO₂

Ex. No. R_(SUB1)  910 3-isopropyl  911 2-Cl, 3-Cl  912 3-CF₃O  913 4-F 914 4-CH₃  915 2-F, 5-Br  916 4-Cl, 3-CH₃CH₂  917 3-CH₃CH₂  918 3-CH₃,5-CH₃  919 3-(CH₃)₃C  920 4-F, 3-CH₃  921 3-Cl, 4-Cl  922 3,4-(CH₂)₄ 923 3-HCF₂CF₂O  924 3-CHF₂O  925 3-(CH₃)₂N  926 3-cyclopropyl  9273-(2-furyl)  928 3-CF₃CF₂  929 4-NH₂  930 3-CH₃, 4-CH₃, 5-CH₃  9314-CH₃CH₂CH₂O  932 2-NO₂

Ex. No. R_(SUB1)  933 3-isopropyl  934 2-Cl, 3-Cl  935 3-CF₃O  936 4-F 937 4-CH₃  938 2-F, 5-Br  939 4-Cl, 3-CH₃CH₂  940 3-CH₃CH₂  941 3-CH₃,5-CH₃  942 3-(CH₃)₃C  943 4-F, 3-CH₃  944 3-Cl, 4-Cl  945 3,4-(CH₂)₄ 946 3-HCF₂CF₂O  947 3-CHF₂O  948 3-(CH₃)₂N  949 3-cyclopropyl  9503-(2-furyl)  951 3-CF₃CF₂  952 4-NH₂  953 3-CH₃, 4-CH₃, 5-CH₃  9544-CH₃CH₂CH₂O  955 2-NO₂

Ex. No. R_(SUB1)  956 3-isopropyl  957 2-Cl, 3-Cl  958 3-CF₃O  959 4-F 960 4-CH₃  961 2-F, 5-Br  962 2-Br, 5-F  963 3-CH₃CH₂  964 3-CH₃, 5-CH₃ 965 3-(CH₃)₃C  966 4-F, 3-CH₃  967 3-Cl, 4-Cl  968 3,4-(CH₂)₄  9693-HCF₂CF₂O  970 3-CHF₂O  971 3-(CH₃)₂N  972 3-cyclopropyl  9733-(2-furyl)  974 3-CF₃CF₂  975 4-NH₂  976 3-CH₃, 4-CH₃, 5-CH₃  9774-CH₃CH₂CH₂O  978 2-NO₂

Ex. No. R_(SUB1)  979 3-isopropyl  980 2-Cl, 3-Cl  981 3-CF₃O  982 4-F 983 4-CH₃  984 2-F, 5-Br  985 4-Cl, 3-CH₃CH₂  986 3-CH₃CH₂  987 3-CH₃,5-CH₃  988 3-(CH₃)₃C  989 4-F, 3-CH₃  990 3-Cl, 4-Cl  991 3,4-(CH₂)₄ 992 3-HCF₂CF₂O  993 3-CHF₂O  994 3-(CH₃)₂N  995 3-cyclopropyl  9963-(2-furyl)  997 3-CF₃CF₂  998 4-NH₂  999 3-CH₃, 4-CH₃, 5-CH₃ 10004-CH₃CH₂CH₂O 1001 2-NO₂

Ex. No. R_(SUB1) 1002 3-isopropyl 1003 2-Cl, 3-Cl 1004 3-CF₃O 1005 4-F1006 4-CH₃ 1007 2-F, 5-Br 1008 4-Cl, 3-CH₃CH₂ 1009 3-CH₃CH₂ 1010 3-CH₃,5-CH₃ 1011 3-(CH₃)₃C 1012 4-F, 3-CH₃ 1013 3-Cl, 4-Cl 1014 3,4-(CH₂)₄1015 3-HCF₂CF₂O 1016 3-CHF₂O 1017 3-(CH₃)₂N 1018 3-cyclopropyl 10193-(2-furyl) 1020 3-CF₃CF₂ 1021 4-NH₂ 1022 3-CH₃, 4-CH₃, 5-CH₃ 10234-CH₃CH₂CH₂O 1024 2-NO₂

Ex. No. R_(SUB1) 1025 3-isopropyl 1026 2-Cl, 3-Cl 1027 3-CF₃O 1028 4-F1029 4-CH₃ 1030 2-F, 5-Br 1031 4-Cl, 3-CH₃CH₂ 1032 3-CH₃CH₂ 1033 3-CH₃,5-CH₃ 1034 3-(CH₃)₃C 1035 4-F, 3-CH₃ 1036 3-Cl, 4-Cl 1037 3,4-(CH₂)₄1038 3-HCF₂CF₂O 1039 3-CHF₂O 1040 3-(CH₃)₂N 1041 3-cyclopropyl 10423-(2-furyl) 1043 3-CF₃CF₂ 1044 4-NH₂ 1045 3-CH₃, 4-CH₃, 5-CH₃ 10464-CH₃CH₂CH₂O 1047 2-NO₂

Ex. No. R_(SUB2) 1048 3-CF₃O-benzyloxy 1049 3-CF₃-benzyloxy 1050 3-F,5-F-benzyloxy 1051 cyclohexylmethyleneoxy 1052 benzyloxy 1053 3-CF₃,5-CF₃-benzyloxy 1054 4-CF₃O-benzyloxy 1055 4-CH₃CH₂-benzyloxy 1056isopropoxy 1057 3-CF₃-benzyl 1058 isopropylthio 1059 cyclopentoxy 10603-Cl-5-pyridinyloxy 1061 3-CF₃S-benzyloxy 1062 3-CH₃, 4-CH₃-benzyloxy1063 2-F, 3-CF₃-benzyloxy 1064 3-F, 5-CF₃-benzyloxy 10654-(CH₃)₂CH-benzyloxy 1066 1-phenylethoxy 1067 4-F, 3-CH₃-benzoyl 10683-CF₃-phenyl- 1069 4-CH₃O-phenylamino- 1070 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1071 3-CF₃O-benzyloxy 1072 3-CF₃-benzyloxy 1073 3-F,5-F-benzyloxy 1074 cyclohexylmethyleneoxy 1075 benzyloxy 1076 3-CF₃,5-CF₃-benzyloxy 1077 4-CF₃O-benzyloxy 1078 4-CH₃CH₂-benzyloxy 1079isopropoxy 1080 3-CF₃-benzyl 1081 isopropylthio 1082 cyclopentoxy 10833-Cl-5-pyridinyloxy 1084 3-CF₃S-benzyloxy 1085 3-CH₃, 4-CH₃-benzyloxy1086 2-F, 3-CF₃-benzyloxy 1087 3-F, 5-CF₃-benzyloxy 10884-(CH₃)₂CH-benzyloxy 1089 1-phenylethoxy 1090 4-F, 3-CH₃-benzoyl 10913-CF₃-phenyl- 1092 4-CH₃O-phenylamino- 1093 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1094 3-CF₃O-benzyloxy 1095 3-CF₃-benzyloxy 1096 3-F,5-F-benzyloxy 1097 cyclohexylmethyleneoxy 1098 benzyloxy 1099 3-CF₃,5-CF₃-benzyloxy 1100 4-CF₃O-benzyloxy 1101 4-CH₃CH₂-benzyloxy 1102isopropoxy 1103 3-CF₃-benzyl 1104 isopropylthio 1105 cyclopentoxy 11063-Cl-5-pyridinyloxy 1107 3-CF₃S-benzyloxy 1108 3-CH₃, 4-CH₃-benzyloxy1109 2-F, 3-CF₃-benzyloxy 1110 3-F, 5-CF₃-benzyloxy 11114-(CH₃)₂CH-benzyloxy 1112 1-phenylethoxy 1113 4-F, 3-CH₃-benzoyl 11143-CF₃-phenyl- 1115 4-CH₃O-phenylamino- 1116 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1117 3-CF₃O-benzyloxy 1118 3-CF₃-benzyloxy 1119 3-F,5-F-benzyloxy 1120 cyclohexylmethyleneoxy 1121 benzyloxy 1122 3-CF₃,5-CF₃-benzyloxy 1123 4-CF₃O-benzyloxy 1124 4-CH₃CH₂-benzyloxy 1125isopropoxy 1126 3-CF₃-benzyl 1127 isopropylthio 1128 cyclopentoxy 11293-Cl-5-pyridinyloxy 1130 3-CF₃S-benzyloxy 1131 3-CH₃, 4-CH₃-benzyloxy1132 2-F, 3-CF₃-benzyloxy 1133 3-F, 5-CF₃-benzyloxy 11344-(CH₃)₂CH-benzyloxy 1135 1-phenylethoxy 1136 4-F, 3-CH₃-benzoyl 11373-CF₃-phenyl- 1138 4-CH₃O-phenylamino- 1139 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1140 3-CF₃O-benzyloxy 1141 3-CF₃-benzyloxy 1142 3-F,5-F-benzyloxy 1143 cyclohexylmethyleneoxy 1144 benzyloxy 1145 3-CF₃,5-CF₃-benzyloxy 1146 4-CF₃O-benzyloxy 1147 4-CH₃CH₂-benzyloxy 1148isopropoxy 1149 3-CF₃-benzyl 1150 isopropylthio 1151 cyclopentoxy 11523-Cl-5-pyridinyloxy 1153 3-CF₃S-benzyloxy 1154 3-CH₃, 4-CH₃-benzyloxy1155 2-F, 3-CF₃-benzyloxy 1156 3-F, 5-CF₃-benzyloxy 11574-(CH₃)₂CH-benzyloxy 1158 1-phenylethoxy 1159 4-F, 3-CH₃-benzoyl 11603-CF₃-phenyl- 1161 4-CH₃O-phenylamino- 1162 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1163 3-CF₃O-benzyloxy 1164 3-CF₃-benzyloxy 1165 3-F,5-F-benzyloxy 1166 cyclohexylmethyleneoxy 1167 benzyloxy 1168 3-CF₃,5-CF₃-benzyloxy 1169 4-CF₃O-benzyloxy 1170 4-CH₃CH₂-benzyloxy 1171isopropoxy 1172 3-CF₃-benzyl 1173 isopropylthio 1174 cyclopentoxy 11753-Cl-5-pyridinyloxy 1176 3-CF₃S-benzyloxy 1177 3-CH₃, 4-CH₃-benzyloxy1178 2-F, 3-CF₃-benzyloxy 1179 3-F, 5-CF₃-benzyloxy 11804-(CH₃)₂CH-benzyloxy 1181 1-phenylethoxy 1182 4-F, 3-CH₃-benzoyl 11833-CF₃-phenyl- 1184 4-CH₃O-phenylamino- 1185 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1186 3-CF₃O-benzyloxy 1187 3-CF₃-benzyloxy 1188 3-F,5-F-benzyloxy 1189 cyclohexylmethyleneoxy 1190 benzyloxy 1191 3-CF₃,5-CF₃-benzyloxy 1192 4-CF₃O-benzyloxy 1193 4-CH₃CH₂-benzyloxy 1194isopropoxy 1195 3-CF₃-benzyl 1196 isopropylthio 1197 cyclopentoxy 11983-Cl-5-pyridinyloxy 1199 3-CF₃S-benzyloxy 1200 3-CH₃, 4-CH₃-benzyloxy1201 2-F, 3-CF₃-benzyloxy 1202 3-F, 5-CF₃-benzyloxy 12034-(CH₃)₂CH-benzyloxy 1204 1-phenylethoxy 1205 4-F, 3-CH₃-benzoyl 12063-CF₃-phenyl- 1207 4-CH₃O-phenylamino- 1208 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1209 3-CF₃O-benzyloxy 1210 3-CF₃-benzyloxy 1211 3-F,5-F-benzyloxy 1212 cyclohexylmethyleneoxy 1213 benzyloxy 1214 3-CF₃,5-CF₃-benzyloxy 1215 4-CF₃O-benzyloxy 1216 4-CH₃CH₂-benzyloxy 1217isopropoxy 1218 3-CF₃-benzyl 1219 isopropylthio 1220 cyclopentoxy 12213-Cl-5-pyridinyloxy 1222 3-CF₃S-benzyloxy 1223 3-CH₃, 4-CH₃-benzyloxy1224 2-F, 3-CF₃-benzyloxy 1225 3-F, 5-CF₃-benzyloxy 12264-(CH₃)₂CH-benzyloxy 1227 1-phenylethoxy 1228 4-F, 3-CH₃-benzoyl 12293-CF₃-phenyl- 1230 4-CH₃O-phenylamino- 1231 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1232 3-CF₃O-benzyloxy 1233 3-CF₃-benzyloxy 1234 3-F,5-F-benzyloxy 1235 cyclohexylmethyleneoxy 1236 benzyloxy 1237 3-CF₃,5-CF₃-benzyloxy 1238 4-CF₃O-benzyloxy 1239 4-CH₃CH₂-benzyloxy 1240isopropoxy 1241 3-CF₃-benzyl 1242 isopropylthio 1243 cyclopentoxy 12443-Cl-5-pyridinyloxy 1245 3-CF₃S-benzyloxy 1246 3-CH₃, 4-CH₃-benzyloxy1247 2-F, 3-CF₃-benzyloxy 1248 3-F, 5-CF₃-benzyloxy 12494-(CH₃)₂CH-benzyloxy 1250 1-phenylethoxy 1251 4-F, 3-CH₃-benzoyl 12523-CF₃-phenyl- 1253 4-CH₃O-phenylamino- 1254 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1255 3-CF₃O-benzyloxy 1256 3-CF₃-benzyloxy 1257 3-F,5-F-benzyloxy 1258 cyclohexylmethyleneoxy 1259 benzyloxy 1260 3-CF₃,5-CF₃-benzyloxy 1261 4-CF₃O-benzyloxy 1262 4-CH₃CH₂-benzyloxy 1263isopropoxy 1264 3-CF₃-benzyl 1265 isopropylthio 1266 cyclopentoxy 12673-Cl-5-pyridinyloxy 1268 3-CF₃S-benzyloxy 1269 3-CH₃, 4-CH₃-benzyloxy1270 2-F, 3-CF₃-benzyloxy 1271 3-F, 5-CF₃-benzyloxy 12724-(CH₃)₂CH-benzyloxy 1273 1-phenylethoxy 1274 4-F, 3-CH₃-benzoyl 12753-CF₃-phenyl- 1276 4-CH₃O-phenylamino- 1277 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1278 3-CF₃O-benzyloxy 1279 3-CF₃-benzyloxy 1280 3-F,5-F-benzyloxy 1281 cyclohexylmethyleneoxy 1282 benzyloxy 1283 3-CF₃,5-CF₃-benzyloxy 1284 4-CF₃O-benzyloxy 1285 4-CH₃CH₂-benzyloxy 1286isopropoxy 1287 3-CF₃-benzyl 1288 isopropylthio 1289 cyclopentoxy 12903-Cl-5-pyridinyloxy 1291 3-CF₃S-benzyloxy 1292 3-CH₃, 4-CH₃-benzyloxy1293 2-F, 3-CF₃-benzyloxy 1294 3-F, 5-CF₃-benzyloxy 12954-(CH₃)₂CH-benzyloxy 1296 1-phenylethoxy 1297 4-F, 3-CH₃-benzoyl 12983-CF₃-phenyl- 1299 4-CH₃O-phenylamino- 1300 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1301 3-CF₃O-benzyloxy 1302 3-CF₃-benzyloxy 1303 3-F,5-F-benzyloxy 1304 cyclohexylmethyleneoxy 1305 benzyloxy 1306 3-CF₃,5-CF₃-benzyloxy 1307 4-CF₃O-benzyloxy 1308 4-CH₃CH₂-benzyloxy 1309isopropoxy 1310 3-CF₃-benzyl 1311 isopropylthio 1312 cyclopentoxy 13133-Cl-5-pyridinyloxy 1314 3-CF₃S-benzyloxy 1315 3-CH₃, 4-CH₃-benzyloxy1316 2-F, 3-CF₃-benzyloxy 1317 3-F, 5-CF₃-benzyloxy 13184-(CH₃)₂CH-benzyloxy 1319 1-phenylethoxy 1320 4-F, 3-CH₃-benzoyl 13213-CF₃-phenyl- 1322 4-CH₃O-phenylamino- 1323 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1324 3-CF₃O-benzyloxy 1325 3-CF₃-benzyloxy 1326 3-F,5-F-benzyloxy 1327 cyclohexylmethyleneoxy 1328 benzyloxy 1329 3-CF₃,5-CF₃-benzyloxy 1330 4-CF₃O-benzyloxy 1331 4-CH₃CH₂-benzyloxy 1332isopropoxy 1333 3-CF₃-benzyl 1334 isopropylthio 1335 cyclopentoxy 13363-Cl-5-pyridinyloxy 1337 3-CF₃S-benzyloxy 1338 3-CH₃, 4-CH₃-benzyloxy1339 2-F, 3-CF₃-benzyloxy 1340 3-F, 5-CF₃-benzyloxy 13414-(CH₃)₂CH-benzyloxy 1342 1-phenylethoxy 1343 4-F, 3-CH₃-benzoyl 13443-CF₃-phenyl- 1345 4-CH₃O-phenylamino- 1346 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1347 3-CF₃O-benzyloxy 1348 3-CF₃-benzyloxy 1349 3-F,5-F-benzyloxy 1350 cyclohexylmethyleneoxy 1351 benzyloxy 1352 3-CF₃,5-CF₃-benzyloxy 1353 4-CF₃O-benzyloxy 1354 4-CH₃CH₂-benzyloxy 1355isopropoxy 1356 3-CF₃-benzyl 1357 isopropylthio 1358 cyclopentoxy 13593-Cl-5-pyridinyloxy 1360 3-CF₃S-benzyloxy 1361 3-CH₃, 4-CH₃-benzyloxy1362 2-F, 3-CF₃-benzyloxy 1363 3-F, 5-CF₃-benzyloxy 13644-(CH₃)₂CH-benzyloxy 1365 1-phenylethoxy 1366 4-F, 3-CH₃-benzoyl 13673-CF₃-phenyl- 1368 4-CH₃O-phenylamino- 1369 4-NO₂-phenylthio-

Ex. No. R_(SUB2) 1370 3-CF₃O-benzyloxy 1371 3-CF₃-benzyloxy 1372 3-F,5-F-benzyloxy 1373 cyclohexylmethyleneoxy 1374 benzyloxy 1375 3-CF₃,5-CF₃-benzyloxy 1376 4-CF₃O-benzyloxy 1377 4-CH₃CH₂-benzyloxy 1378isopropoxy 1379 3-CF₃-benzyl 1380 isopropylthio 1381 cyclopentoxy 13823-Cl-5-pyridinyloxy 1383 3-CF₃S-benzyloxy 1384 3-CH₃, 4-CH₃-benzyloxy1385 2-F, 3-CF₃-benzyloxy 1386 3-F, 5-CF₃-benzyloxy 13874-(CH₃)₂CH-benzyloxy 1388 1-phenylethoxy 1389 4-F, 3-CH₃-benzoyl 13903-CF₃-phenyl- 1391 4-CH₃O-phenylamino- 1392 4-NO₂-phenylthio-

Example Table 50. Substituted4-[N-(aryl)-[(aryl)methyl]amino]-1,1,1,2,2-pentafluoro-3-butanols.

Ex. No. R_(SUB1) Ex. No. R_(SUB2) 1393 3-isopropyl 1416 3-CF₃O—benzyloxy1394 2-Cl, 3-Cl 1417 3-CF₃—benzyloxy 1395 3-CF₃O 1418 3-F, 5-F—benzyloxy1396 4-F 1419 cyclohexylmethyleneoxy 1997 4-CH₃ 1420 benzyloxy 1398 2-F,5-Br 1421 3-CF₃, 5-CF₃—benzyloxy 1399 4-Cl, 3-CH₃CH₂ 14224-CF₃O—benzyloxy 1400 3-CH₃CH₂ 1423 4-CH₃CH₂—benzyloxy 1401 3-CH₃, 5-CH₃1424 isopropoxy 1402 3-(CH₃)₃C 1425 3-CF₃—benzyl 1403 4-F, 3-CH₃ 1426isopropylthio 1404 3-Cl, 4-Cl 1427 cyclopentoxy 1405 3,4-(CH₂)₄ 14283-Cl-5-pyridinyloxy 1406 3-HCF₂CF₂O 1429 3-CF₃S—benzyloxy 1407 3-CHF₂O1430 3-CH₃, 4-CH₃—benzyloxy 1408 3-(CH₃)₂N 1431 2-F, 3-CF₃—benzyloxy1409 3-cyclopropyl 1432 3-F, 5-CF₃—benzyloxy 1410 3-(2-furyl) 14334-(CH₃)₂CH—benzyloxy 1411 3-CF₃CF₂ 1434 1-phenylethoxy 1412 4-NH₂ 14354-F, 3-CH₃—benzoyl 1413 3-CH₃, 4-CH₃, 5-CH₃ 1436 3-CF₃—phenyl— 14144-CH₃CH₂CH₂O 1437 4-CH₃O—phenylamino— 1415 2-NO₂ 1438 4-NO₂—phenylthio—

Example Table 51. Substituted3-[N-(aryl)-[(aryl)oxy]amino]-1,1,1-trifluoro-2-propanols.

Ex. No. R_(SUB1) Ex. No. R_(SUB2) 1439 3-isopropyl 1462 3-CF₃O—benzyloxy1440 2-Cl, 3-Cl 1463 3-CF₃—benzyloxy 1441 3-CF₃O 1464 3-F, 5-F—benzyloxy1442 4-F 1465 cyclohexylmethyleneoxy 1443 4-CH₃ 1466 benzyloxy 1444 2-F,5-Br 1467 3-CF₃, 5-CF₃—benzyloxy 1445 4-Cl, 3-CH₃CH₂ 14684-CF₃O—benzyloxy 1446 3-CH₃CH₂ 1469 4-CH₃CH₂—benzyloxy 1447 3-CH₃, 5-CH₃1470 isopropoxy 1448 3-(CH₃)₃C 1471 3-CF₃—benzyl 1449 4-F, 3-CH₃ 1472isopropylthio 1450 3-Cl, 4-Cl 1473 cyclopentoxy 1451 3,4-(CH₂)₄ 14743-Cl-5-pyridinyloxy 1452 3-HCF₂CF₂O 1475 3-CF₃S—benzyloxy 1453 3-CHF₂O1476 3-CH₃, 4-CH₃—benzyloxy 1454 3-(CH₃)₂N 1477 2-F, 3-CF₃—benzyloxy1455 3-cyclopropyl 1478 3-F, 5-CF₃—benzyloxy 1456 3-(2-furyl) 14794-(CH₃)₂CH—benzyloxy 1457 3-CF₃CF₂ 1480 1-phenylethoxy 1458 4-NH₂ 14814-F, 3-CH₃—benzoyl 1459 3-CH₃, 4-CH₃, 5-CH₃ 1482 3-CF₃—phenyl— 14604-CH₃CH₂CH₂O 1483 4-CH₃O—phenylamino— 1461 2-NO₂ 1484 4-NO₂—phenylthio—

Example Table 52. Substituted3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-butanols.

Ex. No. R_(SUB1) Ex. No. R_(SUB2) 1485 3-isopropyl 1531 3-CF₃O—benzyloxy1486 2-Cl, 3-Cl 1532 3-CF₃—benzyloxy 1487 3-CF₃C 1533 3-F, 5-F—benzyloxy1488 4-F 1534 cyclohexylmethyleneoxy 1489 4-CH₃ 1535 benzyloxy 1490 2-F,5-Br 1536 3-CF₃, 5-CF₃—benzyloxy 1491 4-Cl, 3-CH₃CH₂ 15374-CF₃O—benzyloxy 1492 3-CH₃CH₂ 1538 4-CH₃CH₂—benzyloxy 1493 3-CH₃, 5-CH₃1539 isopropoxy 1494 3-(CH₃)₃C 1540 3-CF₃—benzyl 1495 4-F, 3-CH₃ 1541isopropylthio 1496 3-Cl, 4-Cl 1542 cyclopentoxy 1497 3,4-(CH₂)₄ 15433-Cl-5-pyridinyloxy 1498 3-HCF₂CF₂O 1544 3-CF₃S—benzyloxy 1499 3-CHF₂O1545 3-CH₃, 4-CH₃—benzyloxy 1500 3-(CH₃)₂N 1546 2-F, 3-CF₃—benzyloxy1501 3-cyclopropyl 1547 3-F, 5-CF₃—benzyloxy 1502 3-(2-furyl) 15484-(CH₃)₂CH—benzyloxy 1503 3-CF₃CF₂ 1549 1-phenylethoxy 1504 4-NH₂ 15504-F, 3-CH₃—benzoyl 1505 3-CH₃, 4-CH₃, 5-CH₃ 1551 3-CF₃—phenyl— 15064-CH₃CH₂CH₂O 1552 4-CH₃O—phenylamino— 1507 2-NO₂ 1553 4-NO₂—phenylthio—1508 3-isopropyl 1554 3-CF₃O—benzyloxy 1509 2-Cl, 3-Cl 15553-CF₃—benzyloxy 1510 3-CF₃O 1556 3-F, 5-F—benzyloxy 1511 4-F 1557cyclohexylmethyleneoxy 1512 4-CH₃ 1558 benzyloxy 1513 2-F, 5-Br 15593-CF₃, 5-CF₃—benzyloxy 1514 4-Cl, 3-CH₃CH₂ 1560 4-CF₃O—benzyloxy 15153-CH₃CH₂ 1561 4-CH₃CH₂—benzyloxy 1516 3-CH₃, 5-CH₃ 1562 isopropoxy 15173-(CH₃)₃C 1563 3-CF₃—benzyl 1518 4-F, 3-CH₃ 1564 isopropylthio 15193-Cl, 4-Cl 1565 cyclopentoxy 1520 3,4-(CH₂)₄ 1566 3-Cl-5-pyridinyloxy1521 3-HCF₂CF₂O 1567 3-CF₃S—benzyloxy 1522 3-CHF₂O 1568 3-CH₃,4-CH₃—benzyloxy 1523 3-(CH₃)₂N 1569 2-F, 3-CF₃—benzyloxy 15243-cyclopropyl 1570 3-F, 5-CF₃—benzyloxy 1525 3-(2-furyl) 15714-(CH₃)₂CH—benzyloxy 1526 3-CF₃CF₂ 1572 1-phenylethoxy 1527 4-NH₂ 15734-F, 3-CH₃—benzoyl 1528 3-CH₃, 4-CH₃, 5-CH₃ 1574 3-CF₃—phenyl— 15294-CH₃CH₂CH₂O 1575 4-CH₃O—phenylamino— 1530 2-NO₂ 1576 4-NO₂—phenylthio—

Example Table 53. Substituted3-[N,N′-(diaryl)amino]-1,1,1,2,2-pentafluoro-2-propanols.

Ex. No. R_(SUB1) Ex. No. R_(SUB2) 1577 3-isopropyl 1600 3-CF₃O—benzyloxy1578 2-Cl, 3-Cl 1601 3-CF₃—benzyloxy 1579 3-CF₃O 1602 3-F, 5-F—benzyloxy1580 4-F 1603 cyclohexylmethyleneoxy 1581 4-CH₃ 1604 benzyloxy 1582 2-F,5-Br 1605 3-CF₃, 5-CF₃—benzyloxy 1583 4-Cl, 3-CH₃CH₂ 16064-CF₃O—benzyloxy 1584 3-CH₃CH₂ 1607 4-CH₃CH₂—benzyloxy 1585 3-CH₃, 5-CH₃1608 isopropoxy 1586 3-(CH₃)₃C 1609 3-CF₃—benzyl 1587 4-F, 3-CH₃ 1610isopropylthio 1588 3-Cl, 4-Cl 1611 cyclopentoxy 1589 3,4-(CH₂)₄ 16123-Cl-5-pyridinyloxy 1590 3-HCF₂CF₂O 1613 3-CF₃S—benzyloxy 1591 3-CHF₂O1614 3-CH₃, 4-CH₃—benzyloxy 1592 3-(CH₃)₂N 1615 2-F, 3-CF₃—benzyloxy1593 3-cyclopropyl 1616 3-F, 5-CF₃—benzyloxy 1594 3-(2-furyl) 16174-(CH₃)₂CH—benzyloxy 1595 3-CF₃CF₂ 1618 1-phenylethoxy 1596 4-NH₂ 16194-F, 3-CH₃—benzoyl 1597 3-CH₃, 4-CH₃, 5-CH₃ 1620 3-CF₃—phenyl 15984-CH₃CH₂CH₂O 1621 4-CH₃O—phenylamino 1599 2-NO₂ 1622 4-NO₂—phenylthio

Example Table 54. Substituted2-[N-(aryl)-[(aryl)methyl]amino]-1-trifluoromethylcyclopentanols.

Ex. No. R_(SUB1) Ex. No. R_(SUB2) 1623 3-isopropyl 1646 3-CF₃O—benzyloxy1624 2-Cl, 3-Cl 1647 3-CF₃—benzyloxy 1625 3-CF₃O 1648 3-F, 5-F—benzyloxy1626 4-F 1649 cyclohexylmethyleneoxy 1627 4-CH₃ 1650 benzyloxy 1628 2-F,5-Br 1651 3-CF₃, 5-CF₃—benzyloxy 1629 4-Cl, 3-CH₃CH₂ 16524-CF₃O—benzyloxy 1630 3-CH₃CH₂ 1653 4-CH₃CH₂—benzyloxy 1631 3-CH₃, 5-CH₃1654 isopropoxy 1632 3-(CH₃)₃C 1655 3-CF₃—benzyl 1633 4-F, 3-CH₃ 1656isopropylthio 1634 3-Cl, 4-Cl 1657 cyclopentoxy 1635 3,4-(CH₂)₄ 16583-Cl-5-pyridinyloxy 1636 3-HCF₂CF₂O 1659 3-CF₃S—benzyloxy 1637 3-CHF₂O1660 3-CH₃, 4-CH₃—benzyloxy 1638 3-(CH₃)₂N 1661 2-F, 3-CF₃—benzyloxy1639 3-cyclopropyl 1662 3-F, 5-CF₃—benzyloxy 1640 3-(2-furyl) 16634-(CH₃)₂CH—benzyloxy 1641 3-CF₃CF₂ 1664 1-phenylethoxy 1642 4-NH₂ 16654-F, 3-CH₃—benzoyl 1643 3-CH₃, 4-CH₃, 5-CH₃ 1666 3-CF₃—phenyl— 16444-CH₃CH₂CH₂O 1667 4-CH₃O—phenylamino— 1645 2-NO₂ 1668 4-NO₂—phenylthio—

EXAMPLE 1669

N-(3-phenoxyphenyl)-N-(3,3,3,2-tetrafluoropropyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine

To a solution of3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol(474 mg, 0.00094 mol) in 4.5 mL of dichloromethane at 0° C. was added(diethylamino)sulfur trifluoride (378 mg, 0.0023 mol). The reactionmixture was warmed to room temperature and stirred for 2 h, thenquenched with water and extracted with dichloromethane. The organiclayers were combined, dried over MgSO₄, and concentrated in vacuo. Thecrude product was purified by column chromatography on silica geleluting with 1:9 ethyl acetate in hexane to afford 240 mg (50%) of thedesiredN-(3-phenoxyphenyl)-N-(3,3,3,2-tetra-fluoropropyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamineproduct as a yellow oil. HRMS calcd. for C₂₄H₁₉F₈NO₂: 506.1366 [M+H]⁺,found: 506.1368. ¹H NMR (CDCl₃) δ7.26 (m, 3H), 7.20 (m, 5H), 6.87 (d,2H), 6.62 (d, 1H), 6.50 (s, 1H), 6.49 (d, 1H), 5.87 (t, 1H), 4.89 (d,1H), 4.77-4.52 (m, 1H), 4.73 (d, 1H), 4.60 (s, 2H), ¹⁹F NMR (CDCl₃)δ−69.83 (t, 3F), −88.63 (s, 2F), −137.19 (dt, 2F), −228.82 (1F).

EXAMPLE 1670

2-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-3,3,3-trifluoropropanol

To a dichloromethane (2 mL) solution ofN-[(4-chloro-3-ethyl-phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine(0.25 g, 0.55 mmol) and 2-diazo-3,3,3-trifluoropropionic acidp-nitrophenyl ester (0.14 g, 0.51 mmol) was added solid Rh₂(OAc)₄ (0.015g, 0.034 mmol). The resulting green slurry was stirred at roomtemperature under nitrogen for 24 h. The solvent was removed to give agreen oil, and the crude intermediate was dissolved in THF (4 mL). Thisgreen solution was cooled to 0° C., and a 1.0 M solution of LiAlH₄ inTHF (0.6 mL, 0.6 mmol) was added dropwise. The resulting dark solutionwas stirred for 30 min at 0° C. and quenched by the slow addition ofwater. The reaction mixture was extracted with Et₂O, dried (MgSO₄) andevaporated to give a brown oil. Purification by flash columnchromatography on silica gel eluting with 20% ethyl acetate in hexanegave 0.032 g (11%) of the desired2-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]3,3,3-trifluoropropanolproduct as a light brown oil. HRMS calcd. for C₂₆H₂₃NO₃ClF₇: 566.1333[M+H]⁺, found: 566.1335. ¹H NMR (C₆D₆) δ0.53 (t, 1H), exchangeable withD₂O), 0.93 (t, 3H), 2.43 (t, 2H), 3.33 (m, 2H), 4.11 (s, 2H), 4.13 (m,1H), 5.04 (tt, 1H), 6.4 (m, 3H), 6.55 (t, 1H), 6.7-6.8 (m, 5H), 6.97 (d,1H), 7.04 (s, 1H).

EXAMPLE 1671

N-(3-phenoxyphenyl)-N-(4,4,4-trifluorobutyl)-3-(trifluoromethoxy)benzenemethanamine

EX-1671A) To a solution of 3-phenoxyaniline (10.9 g, 58.8 mmol) in 100mL of cyclohexane was added solid NaH (60% in mineral oil, 1.96 g, 49mmol). Then 3-trifluoromethoxybenzyl bromide (10.0 g, 39.2 mmol) wasadded dropwise under a nitrogen atmosphere, and the mixture was heatedto reflux for 18 h, at which time TLC analysis indicated that no3-trifluoromethoxybenzyl bromide remained. The reaction mixture wascooled to room temperature and quenched with water, then extracted withether. The ether layer was washed with water and brine, then dried overMgSO₄, and evaporated to give crude product. The crude product waspurified by flash column chromatography on silica gel eluting with1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give the desiredN-benzylaniline product, which contained a small portion of dibenzylatedamine. This product was further purified by conversion to thecorresponding HCl salt to give 11.0 g (73%) of the desiredN-(3-phenoxyphenyl)-N-[(3-trifluoromethoxy)phenyl]methyl]aminehydrochloride product. HRMS calcd. for C₂₀H₁₆NO₂F₃: 360.1211 [M+H]⁺,found 360.1208.

The N-(3-phenoxyphenyl)-N-[(3-trifluoromethoxy)phenyl]methyl]aminehydrochloride (1.0 g, 2.5 mmol) product from EX-1671A was dissolved in20 mL of THF under nitrogen. Solid NaNH₂ (50% in xylene, 0.2 g, 2.6mmol) was added, and the mixture was stirred at room temperature. Then1-iodo-4,4,4-trifluorobutone (1.0 g, 4.2 mmol) and additional NaNH₂ (50%in xylene, 0.2 g, 2.6 mmol) was added. The mixture was heated at refluxfor 24 h, at which time HPLC analysis indicated that no secondary aminestarting material remained. The reaction was quenched with water andextracted with ether. The ether layer was washed with water and brine,then dried over MgSO₄. The crude product was purified by flash columnchromatography on silica gel eluting with 1:4:0.01 of ethylacetate:hexane:ammonium hydroxide to give 1.0 g(85%) of the desiredN-(3-phenoxyphenyl)-N-(4,4,4-trifluorobutyl)-3-(trifluoromethoxy)benzene-methanamine product as an off-white oil. ¹H NMR (CDCl₃) δ7.29(m, 3H), 7.09 (m, 4H), 7.01 (s, 1H), 6.95 (d, 2H), 6.43 (d, 1H), 6.36(d, 1H), 6.31 (s, 1H), 4.49 (s, 2H), 3.41 (t, 2H), 2.08 (m, 2H), 1.89(q, 2H). ¹⁹F NMR (CDCl₃) δ−58.18 (s, 3F), −66.44 (t, 3F). Anal. calcd.for C₂₄H₂₁NO₂F₆: C, 61.41; H, 4.51; N, 2.98. Found: C, 61.16, H, 4.53;N, 2.92. HRMS calcd. 470.1555 [M+H]⁺, found: 470.1565.

EXAMPLE 1672

3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanthiol

EX-1672A) A solution of 3-(4-chloro-3-ethylphenoxy)aniline (3.72 g, 15mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (3.33 g, 15 mmol) isprepared in 60 mL of dichloroethane. Acetic acid (0.92 mL, 16.05 mmol)and solid NaBH(OAc)₃ (4.13 g, 19.5 mmol) are added. The mixture isstirred at room temperature for 3 hours, then is acidified with 1 Naqueous HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide,the mixture is extracted with methylene chloride. The organic layer iswashed with brine and water, then dried over anhydrous MgSO₄, andevaporated to give 5.00 g (85%) of the desiredN-(3-(4-chloro-3-ethylphenoxy)phenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amineproduct.

Amine product EX-1672A (8 mmol) and 3,3,3-trifluoromethylthiirane (1.54g, 12 mmol) are dissolved in 1.5 mL of acetonitrile. Ytterbium (III)trifluoromethanesulfonate (0.25 g, 0.4 mmol) is added, and the stirredsolution is warmed to 50° C. under an atmosphere of nitrogen untilcompletion of reaction as is indicated by HPLC analysis showing that nosecondary amine starting material remains. The reaction is quenched withwater and extracted with ether.

The ether layer is washed with water and brine, then is dried overMgSO₄. The crude product is purified by flash column chromatography onsilica gel with a solvent mixture to give the desired aminopropanethiolproduct.

EXAMPLE 1673

3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanamine

Amine product EX-1672A (8 mmol) and 3,3,3-trifluoromethylaziridine (1.33g, 12 mmol) are dissolved in 1.5 mL of acetonitrile. Ytterbium (III)trifluoromethanesulfonate (0.25 g, 0.4 mmol) is added, and the stirredsolution is warmed to 50° C. under an atmosphere of nitrogen untilcompletion of reaction as is indicated by HPLC analysis showing that nosecondary amine starting material remains. The reaction is quenched withwater, the pH is adjusted to 9.5 with 2.5 N sodium hydroxide, and it isextracted with ether. The ether layer is washed with water and brine,then is dried over Na₂CO₃. The crude product is purified by flash columnchromatography on silica gel with a solvent mixture to give the desiredpropanediamine product.

BIOASSAYS CETP Activity In Vitro

Assay of CETP Inhibition Using Purified Components (Reconstituted BufferAssay)

The ability of compounds to inhibit CETP activity was assessed using anin vitro assay that measured the rate of transfer of radiolabeledcholesteryl ester ([³H]CE) from HDL donor particles to LDL acceptorparticles. Details of the assay are provided by Glenn, K. C. et al.(Glenn and Melton, “Quantification of Cholesteryl Ester Transfer Protein(CETP): A) CETP Activity and B) Immunochemical Assay of CETP Protein,”Meth. Enzymol., 263, 339-351 (1996)). Human recombinant CETP can beobtained from the serum-free conditioned medium of CHO cells transfectedwith a cDNA for CETP and purified as described by Wang, S. et al. (J.Biol. Chem. 267, 17487-17490 (1992)). To measure CETP activity,[³H]CE-labeled-HDL, LDL, CETP and assay buffer (50 mMtris(hydroxymethyl)aminomethane, pH 7.4; 150 mM sodium chloride; 2 mMethylenediamine-tetraacetic acid (EDTA); 1% bovine serum albumin) wereincubated in a final volume of 200 μL, for 2 hours at 37° C. in 96 wellplates. Inhibitors were included in the assay by diluting from a 10 mMDMSO stock solution into 16% (v/v) aqueous DMSO so that the finalconcentration of inhibitor was 800 μM. The inhibitors were then diluted1:1 with CETP in assay buffer, and then 25 μL of that solution was mixedwith 175 μL of lipoprotein pool for assay. Following incubation, LDL wasdifferentially precipitated by the addition of 50 μL of 1% (w/v) dextransulfate/0.5 M magnesium chloride, mixed by vortex, and incubated at roomtemperature for 10 minutes. A potion of the solution (200 μL) wastransferred to a filter plate (Millipore). After filtration, theradioactivity present in the precipitated LDL was measured by liquidscintillation counting. Correction for non-specific transfer orprecipitation was made by including samples that do not contain CETP.The rate of [³H]CE transfer using this assay was linear with respect totime and CETP concentration, up to 25-30% of ³H]CE transferred.

The potency of test compounds was determined by performing the abovedescribed assay in the presence of varying concentrations of the testcompounds and determining the concentration required for 50% inhibitionof transfer of [³H ]CE from HDL to LDL. This value was defined as theIC₅₀. The IC₅₀ values determined from this assay are accurate when theIC₅₀ is greater than 10 nM. In the case where compounds have greaterinhibitory potency, accurate measurements of IC₅₀ may be determinedusing longer incubation times (up to 18 hours) and lower finalconcentrations of CETP (<50 nM).

Examples of IC₅₀ values determined by these methods are specified inTable 9.

Assay of CETP Inhibition in Human Plasma

Blood was obtained from healthy volunteers, recruited from the personnelof Monsanto Company, Saint Louis, Mo. Blood was collected in tubescontaining EDTA (EDTA plasma pool). The EDTA human plasma pool,previously stored at −20° C., was thawed at room temperature andcentrifuged for 5 minutes to remove any particulate matter. TritiatedHDL, radiolabeled in the cholesteryl ester moiety ([³H]CE-HDL) asdescribed by Morton and Zilversmit (J. Biol. Chem., 256. 11992-95(1981)), was added to the plasma to a final concentration of 25 μg/mLcholesterol. Equal volumes (396 μL) of the plasma containing the[³H]CE-HDL were added by pipette into micro tubes (Titertube®, Bio-Radlaboratories, Hercules, Calif.). Inhibitor compounds, dissolved as 20-50mM stock solutions in DMSO, were serially diluted in DMSO (or analternative solvent in some cases, such as dimethylformamide orethanol). Four μL of each of the serial dilutions of inhibitor compoundsor DMSO alone were then added to each of the tubes containing plasma(396 μL). After mixing, triplicate aliquots (100 μL) from each plasmatube were then transferred to wells of 96-well round-bottomedpolystyrene microtiter plates (Corning, Corning, N.Y.). Plates weresealed with plastic film and incubated at 37° C. for 4 hours. “Test”samples contained plasma with dilutions of inhibitor compounds.“Control” samples contained plasma with DMSO diluted to the sameconcentration as the test samples, but without inhibitor. “Blank”samples were prepared as “control” samples, but were left in the microtubes at 4° C. for the 4 hour incubation and were then added to themicrotiter wells at the end of the incubation period. VLDL and LDL wereprecipitated by the addition of 10 μL of precipitating reagent (1% (w/v)dextran sulfate (Dextralip50)/0.5 M magnesium chloride, pH 7.4) to allwells. The wells were mixed on a plate mixer and then incubated atambient temperature for 10 min. The plates were then centrifuged at1000×g for 30 min at 10° C. The supernatants (50 μL) from each well werethen transferred to Picoplate™96 plate wells (Packard, Meriden, Conn.)containing Microscint™-40 (Packard. Meriden, Conn.). The plates wereheat-sealed (TopSeal™-P, Packard, Meriden, Conn.) according to themanufacturer's directions and mixed for 30 min. Radioactivity wasmeasured on a microplate scintillation counter (TopCount, Packard,Meriden, Conn.). The maximum percentage transfer in the control wells (%transfer) was determined using the following equation:${\% \quad {Transfer}} = \frac{\left\lbrack {{dpm}_{blank} - {dpm}_{control}} \right\rbrack \times 100}{{dpm}_{blank}}$

The percentage of transfer relative to the control (% control) wasdetermined in the wells containing inhibitor compounds was determined asfollows:${\% \quad {Control}} = \frac{\left\lbrack {{dpm}_{blank} - {dpm}_{test}} \right\rbrack \times 100}{{dpm}_{blank} - {dpm}_{control}}$

IC₅₀ values were then calculated from plots of % control versusconcentration of inhibitor compound. IC₅₀ values were determined as theconcentration of inhibitor compound inhibiting transfer of [³H]CE fromthe supernatant [³H]CE-HDL to the precipitated VLDL and LDL by 50%compared to the transfer obtained in the control wells.

Examples of IC₅₀ values determined by this method are specified in Table10.

TABLE 9 Inhibition of CETP Activity by Examples in Reconstituted BufferAssay. Ex. IC₅₀ Ex. IC₅₀ Ex. IC₅₀ No. (μM) No. (μM) No. (μM) 249 0.020419 0.19 425 0.34 244 0.029 230 0.20 514 0.34 634 0.032 248 0.20 2370.35 221 0.034 266 0.20 399 0.35 229 0.034 378 0.20 645 0.35 660 0.040488 0.20 225 0.37 630 0.050 241 0.21 247 0.37 629 0.054 245 0.21 4730.37 372 0.062 400 0.21 216 0.39 233 0.063 639 0.21 243 0.39 234 0.069226 0.22 636 0.39 252 0.075 373 0.22 650 0.41 242 0.076 377 0.23 3850.42 277 0.076 253 0.24 427 0.42 256 0.079 411 0.25 436 0.42 232 0.080638 0.26 509 0.42 278 0.098 222 0.27 619 0.42 379 0.098 240 0.27 5210.43 258 0.099 374 0.27 250 0.44 238 0.12 420 0.27 429 0.44 227 0.13 2230.29 658 0.44 423 0.13 415 0.29 637 0.47 656 0.13 235 0.31 592 0.48 2140.14 607 0.31 251 0.49 628 0.14 265 0.33 421 0.49 281 0.14 402 0.33 2710.50 224 0.16 489 0.33 287 0.50 279 0.16 231 0.34 550 0.50 401 0.18 2750.34 416 0.51 410 0.19 390 0.34 438 0.52 647 0.52 518 0.79 442 1.1 5980.54 397 0.81 595 1.1 567 0.55 393 0.82 642 1.1 391 0.56 499 0.83 450B1.1 559 0.56 648 0.83 71 1.2 246 0.57 282 0.84 305 1.2 268 0.58 396 0.86381 1.2 527 0.58 581 0.87 441 1.2 269 0.59 294 0.88 446 1.2 292 0.59 5570.88 492 1.2 405 0.60 218 0.91 496 1.2 409 0.61 601 0.91 524 1.2 4750.64 653 0.91 569 1.2 254 0.65 422 0.92 693 1.2 450A 0.66 556 0.92 2861.3 654 0.67 506 0.97 296 1.3 558 0.69 541 0.97 655B 1.3 389 0.70 2740.99 264 1.4 412 0.71 651 0.99 392 1.4 408 0.75 77 1.0 406 1.4 554 0.75267 1.0 522 1.4 280 0.76 293 1.0 526 1.4 525 0.76 439 1.0 568 1.4 5780.76 560 1.0 582 1.4 440 0.77 657 1.0 74 1.5 523 0.77 659 1.0 79 1.5 6460.77 599 1.0 403 1.5 166 0.78 285 1.1 407 1.5 424 0.78 395 1.1 444 1.5593 0.78 398 1.1 495 1.5 456B 1.5 167 2.0 302 2.5 565 1.5 307 2.0 4262.5 652 1.5 597 2.0 519 2.5 699 1.5 315 2.1 555 2.5 91 1.6 404 2.1 5642.5 140 1.6 418 2.1 688 2.5 149 1.6 503 2.1 690 2.5 255 1.6 508 2.1 3092.6 384 1.6 513 2.1 311 2.6 517 1.6 562 2.1 494 2.6 571 1.6 643 2.1 442.7 644 1.6 257 2.2 452 2.7 150 1.7 387 2.2 543 2.7 261 1.7 437 2.2 5662.7 432 1.7 483 2.2 445 2.8 505 1.7 490 2.2 73 3.0 584 1.7 89 2.3 1043.0 1670 1.8 299 2.3 115 3.0 212 1.8 318 2.3 220B 3.0 289 1.8 382 2.3322 3.0 312 1.8 383 2.3 388 3.0 478 1.5 507 2.3 460 3.0 493 1.8 544 2.3464 3.0 515 1.8 580 2.3 516 3.0 561 1.8 608 2.3 691 3.0 570 1.8 128 2.4316 3.1 579 1.8 542 2.4 394 3.1 304 1.9 168 2.5 633 3.1 480 1.9 259 2.5386 3.2 70 2.0 260 2.5 376 3.3 459 3.3 595B 4.5 310 6.6 317 3.4 701 4.5514C 6.6 63 3.5 414 4.6 603 6.7 159 3.5 454 4.6 428 6.8 204 3.5 319 4.7602 6.8 609 3.5 482 4.8 632 6.8 622 3.5 553 4.8 42 7.0 210 3.6 273 4.952 7.0 501 3.6 649 4.9 59 7.0 655 3.6 84 5.0 75 7.0 262 3.7 141 5.0 1277.0 371 3.9 321 5.0 162 7.0 449 3.9 620 5.0 172 7.0 36 4.0 689 5.0 1947.0 43 4.0 60 5.5 346 7.7 66 4.0 433 5.6 617 7.9 87 4.0 502 5.7 26 8.0126 4.0 585 5.8 82 8.0 153 4.0 76 6.0 122 8.0 201 4.0 101 6.0 124 8.0588 4.1 134 6.0 139 8.0 627 4.1 208 6.0 147 8.0 594 4.2 474 6.0 152 8.0606 4.2 239 6.1 453 8.0 448 4.3 512 6.1 290 8.1 640 4.3 591 6.2 625 8.3297 4.4 576 6.4 291 8.4 491 4.4 583 6.4 90 9.0 209 4.5 434B 6.4 112 9.0375 4.5 270 6.5 129 9.0 323 9.0 136 12 67 15 215 9.2 158 12 68 15 4569.2 288 12 98 15 621 9.3 431 12 145 15 447 9.8 462 12 148 15 25 10 46612 185 15 47 10 605 12 186 15 72 10 611 12 198 15 78 10 687 12 200 15131 10 38 13 308 15 146 10 451 13 347 15 163 10 457 13 589 15 193 10 45813 661 15 199 10 461 13 686 15 236 10 463 13 694 15 486 10 596 13 695 15551 10 211 14 514D 15 572 10 314 14 35 16 613 10 504 14 692 16 213 11590 14 612A 16 301 11 19 15 276 17 380 11 23 15 295 17 472 11 39 15 41317 477 11 50 15 417 17 641 11 53 15 1669 17 528B 11 54 15 62 18 1671 1157 15 197 18 31 12 58 15 220 18 41 12 64 15 574 18 92 12 33 15 616 18 5120 106 30 17 45 55 20 138 30 118 45 56 20 195 30 345 45 65 20 520 30 36245 69 20 626 30 604 46 80 20 300 31 529 49 83 20 217 32 22 50 86 20 32032 34 50 113 20 303 33 93 50 135 20 103 35 96 50 137 20 105 35 120 50160 20 348 35 350 50 173 20 352 35 351 50 313 20 468 35 471 50 324 20612 35 662 50 610 20 702 35 697 55 683 20 1 38 3 60 30 22 94 40 4 60 45522 114 40 14 60 61 23 116 40 16 60 192 23 142 40 18 60 587 23 156 40 9560 298 24 196 40 102 60 620A 24.6 335 40 108 60 109 25 357 40 110 60 11725 363 40 203 60 125 25 497 42 685 60 132 25 473B 42 111 65 133 25 528C42 119 70 306 25 528 43 342 70 353 70 435 >50 263 >50 664 70 435B >50284 >50 28 75 443 >50 430 >50 88 75 465 >50 434 >50 107 75 467 >50563 >50 355 75 469 >50 573 >50 85 80 470 >50 575 >50 130 80 476 >50577 >50 143 80 479 >50 586 >50 332 80 484 >50 632A >50 366 80 487 >505 >100 635 80 498 >50 6 >100 665 80 500 >50 7 >100 97 90 511 >50 8 >100100 90 530 >50 9 >100 123 90 531 >50 10 >100 165 90 532 >50 11 >100 20790 533 >50 12 >100 2 100 534 >50 13 >100 45 100 535 >50 15 >100 144 100536 >50 20 >100 333 100 537 >50 21 >100 334 100 538 >50 24 >100 340 100539 >50 27 >100 343 100 540 >50 29 >100 618 100 545 >50 32 >100 663 100546 >50 37 >100 672 100 547 >50 40 >100 696 100 548 >50 46 >100 698 100549 >50 48 >100 49 >100 325 >100 588B >100 81 >100 326 >100 614 >10099 >100 327 >100 615 >100 121 >100 328 >100 631 >100 161 >100 329 >100634C >100 164 >100 330 >100 667 >100 169 >100 331 >100 668 >100 170 >100336 >100 669 >100 171 >100 337 >100 670 >100 174 >100 338 >100 671 >100175 >100 339 >100 673 >100 176 >100 341 >100 674 >100 177 >100 344 >100675 >100 178 >100 349 >100 676 >100 179 >100 354 >100 677 >100 180 >100356 >100 678 >100 181 >100 358 >100 679 >100 182 >100 359 >100 680 >100183 >100 360 >100 681 >100 184 >100 361 >100 682 >100 187 >100 364 >100684 >100 188 >100 365 >100 189 >100 367 >100 190 >100 368 >100 191 >100369 >100 202 >100 370 >100 205 >100 151 >100 206 >100 154 >100 219 >100155 >100 283 >100 157 >100

TABLE 10 Inhibition of CETP Activity by Examples in Human Plasma Assay.Ex. IC₅₀ Ex. IC₅₀ Ex. IC₅₀ No. (μM) No. (μM) No. (μM) 229 0.56 256 7.8554 18 221 0.88 559 8.0 266 21 233 1.0 637 8.0 645 21 234 1.0 245 8.4269 22 660 1.1 489 8.8 287 22 630 1.8 450A 9.0 280 23 249 2.3 265 9.6216 24 402 2.9 240 9.7 377 24 242 3.1 248 10 390 24 399 3.4 275 10 44024 232 3.4 395 10 657 24 629 3.4 396 10 391 25 244 3.8 397 10 251 26 2523.9 281 11 253 27 634 4.1 560 11 267 27 401 4.2 638 11 385 29 488 4.3241 12 438 29 429 4.4 282 12 166 30 619 4.9 373 12 294 30 393 5.0 378 12550 30 639 5.0 654 12 650 30 258 5.2 246 13 658 30 214 5.7 278 13 218 31628 5.7 439 13 250 31 372 5.7 647 13 243 34 405 6.2 436 14 271 34 4006.3 279 15 499 34 277 6.5 274 16 557 34 656 6.9 473 16 128 35 379 7.7247 17 71 36 268 37 42 80 299 >100 475 37 140 80 302 >100 292 38 150 80309 >100 558 38 307 81 311 >100 653 38 601 83 315 >100 374 39 296 86316 >100 77 40 59 100 317 >100 293 42 73 100 321 >100 595 42 43 110322 >100 126 45 201 110 346 >100 74 48 60 120 600 >100 655 48 63 120649 >100 556 49 66 120 686 >100 593 49 75 200 688 >100 642 50 389 >50691 >100 592 52 447 >50 220B >100 699 55 104 >100 595B >100 79 60115 >100 35 >200 87 60 127 >100 36 >200 89 60 131 >100 76 >200 655B 63141 >100 661 >200 70 65 149 >100 664 >200 312 65 168 >100 33 500 659 65204 >100 84 70 208 >100 91 70 209 >100 690 75 210 >100 304 76 219 >100305 76 273 >100 254 77 297 >100

What we claim is:
 1. A method of treating or preventing a CETP-mediated disorder in a subject by administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, said compound being of Formula I:

wherein; X is selected from group consisting of NH, N(OH), and N(alkyl); R₁₆ is hydrido; n is 1 or 2; R₁ is haloalkyl or haloalkoxyalkyl; R₂ is selected from the group consisting of hydrido, hydroxyalkyl, aryl, aralkyl, alkyl, alkenyl, alkynyl, aralkoxyalkyl, aryloxyalkyl, aloxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyloalkenyl, cycloalkenylalkyl, haloalkyl, perhaloaryl, penhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, and heteroaralkyl; R₃ is selected from the group consisting of hydrido, alkyl, alkenyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, and cycloalkenylalkyl; Y is a bond or (C(R₁₄)₂)_(q) wherein q is 1 or 2; Z is a bond or (C(R₁₅)₂)_(q) wherein q is 1 or 2; R₁₄ and R₁₅ are independently hydrido or alkyl; R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano; with the proviso that at least one of R₄, R₅, , R₇, and R₈ is not hydrido or with the proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 2. The method of claim 1, wherein said compound is of Formula I, wherein at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 3. The method of claim 2, wherein said compound is of Formula I, wherein; X is NH; R₁₆ hydrido; n is 1 or 2; R₁ is haloalkyl or haloalkoxyalkyl; R₂ is hydrido; R₃ is hydrido; Y is selected from the group consisting of a bond, CH₂, and CH₂CH₂; Z is selected from the group consisting of a bond, CH₂, and CH₂CH₂; R₄, R₈, R₉, and R₁₃ are independently hydrido or halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxaridoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, aralkyl, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, alkylamino, alkylthio, arylamino, arylthio, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, aroyl, alkyl, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxyalkyl, and heteroaryloxy; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 4. The method of claim 3, wherein said compound is of Formula I, wherein; X is NH; R₁₆ is hydrido; n is 1; R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R₂ is hydrido; R₃₂ hydrido; Y is CH₂ or CH₂CH₂; Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ and R₁₀ are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamnino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazolyl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio; R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy; R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
 5. The method of claim 4, wherein said compound is of Formula I, wherein; X is NH; R₁₆ is hydrido; n is 1; R₁ is selected from the group consisting of trifluoromethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R₂ is hydrido; R₃ is hydrido; Y is CH₂; Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ and R₁₀ are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylamninophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 4-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazolyl-4, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio; R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl; R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
 6. The method of claim 3, wherein said compound is of Formula II:

wherein; R₁ is haloalkyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, heteroaralkoxy, aralkyl, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, alkylthio, arylamino, arylthio, arylsulfonyl, aroyl, alkyl, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxyalkyl, and heteroaryloxy; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 7. The method of claim 6, wherein said compound is of Formula II, wherein; R₁ is trifluoromethyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consisting of cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl, 1,1-bis-trifluoromethyl-1-hydroxymethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl, and trifluoromethylthio; R₆, R₇, R₁₁, and R₁₂ are independently hydrido or fluoro.
 8. The method of claim 7, wherein said compound is of Formula II, wherein; R₁ is trifluoromethyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consisting of 1,1,2,2-tetrafluoroethoxy, pentafluoroethyl, and trifluoromethyl; R₆, R₇, R₁₁, and R₁₂ are independently hydroido or fluoro.
 9. The method of claim 1, wherein said compound is:


10. The method of claim 1 further characterized by treating coronary artery disease in a subject by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 11. The method of claim 1 further characterized by preventing coronary artery disease in a subject by administering a therapeutically effective amount of a compound of claim 19 or a pharmaceutically acceptable salt thereof.
 12. The method of claim 1 further characterized by preventing cerebral vascular accident (CVA) in a subject by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 13. The method of claim 1 further characterized by treating or preventing dyslipidemia in a subject by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 